Immunology of Mycobacterium

Immunology of Mycobacterium
tuberculosis Infections
JONATHAN KEVIN SIA1 and JYOTHI RENGARAJAN2
1
Emory Vaccine Center, Emory University School of Medicine, Emory University, Atlanta, GA 30329;
2
Department of Medicine, Division of Infectious Diseases and Emory Vaccine Center,
Emory University School of Medicine, Emory University, Atlanta, GA 30329
ABSTRACT Tuberculosis (TB) is a serious global public health bacterial replication, is a well-known antimycobacte-
challenge that results in significant morbidity and mortality rial contribution by adaptive immune cells such as CD4
worldwide. TB is caused by infection with the bacilli
and CD8 T cells. Despite pressures from host immunity,
Mycobacterium tuberculosis (M. tuberculosis), which has evolved
a wide variety of strategies in order to thrive within its host.
M. tuberculosis is able to persist in the host. M. tuber-
Understanding the complex interactions between M. tuberculosis culosis infection results in hallmark lesions called gran-
and host immunity can inform the rational design of better ulomas, which are initially aggregates of infected and
TB vaccines and therapeutics. This chapter covers innate and uninfected myeloid cells circumscribed by a lymphocytic
adaptive immunity against M. tuberculosis infection, including cuff. The granuloma is thought to prevent bacterial dis-
insights on bacterial immune evasion and subversion garnered semination to extrapulmonary sites but can also become
from animal models of infection and human studies. In addition, a niche for long-term bacterial persistence. M. tubercu-
this chapter discusses the immunology of the TB granuloma,
losis has evolved myriad strategies to evade and subvert
TB diagnostics, and TB comorbidities. Finally, this chapter
provides a broad overview of the current TB vaccine pipeline. immune responses to persist within a host, and it is be-
coming increasingly clear that the immune response
to M. tuberculosis infection involves contributions from
INTRODUCTION a wide variety of innate and adaptive immune cells. A
Mycobacterium tuberculosis, the etiologic agent of tuber- clearer understanding of the complex cross talk between
culosis (TB), remains a significant global public health M. tuberculosis and host immunity is essential for the
burden (1). In 2016, there were 10.4 million new TB development of efficacious TB vaccines. Despite being
cases reported globally and nearly 1.7 million TB-related
deaths (1). Understanding the host response to M. tu- Received: 30 April 2018, Accepted: 10 May 2018,
Published: 12 July 2019
berculosis infection is a key aspect of efforts to eradi- Editors: Vincent A. Fischetti, The Rockefeller University, New York,
cate TB through the development of effective vaccines NY; Richard P. Novick, Skirball Institute for Molecular Medicine, NYU
and immune therapeutics. M. tuberculosis is an intra- Medical Center, New York, NY; Joseph J. Ferretti, Department of
Microbiology & Immunology, University of Oklahoma Health
cellular pathogen transmitted via inhalation of aerosol- Science Center, Oklahoma City, OK; Daniel A. Portnoy, Department
ized, bacteria-containing droplets. Innate immune cells of Molecular and Cellular Microbiology, University of California,
in the lungs, primarily macrophages, dendritic cells, Berkeley, Berkeley, CA; Miriam Braunstein, Department of
Microbiology and Immunology, University of North Carolina-Chapel
monocytes, and neutrophils, readily phagocytose M. Hill, Chapel Hill, NC, and Julian I. Rood, Infection and Immunity
tuberculosis and are the earliest defenders against the Program, Monash Biomedicine Discovery Institute, Monash
University, Melbourne, Australia
pathogen. The transformation of bacteria-containing
Citation: Sia JK, Rengarajan J.2019.Immunology of Mycobacterium
phagosomes into acidified, antimicrobial compartments tuberculosis infections. Microbiol Spectrum 7(4):GPP3-0022-2018.
is a central tenet of defense against M. tuberculosis. doi:10.1128/microbiolspec.GPP3-0022-2018.
In this regard, the production of interferon-γ (IFN-γ), Correspondence: Jyothi Rengarajan, [email protected]
© 2019 American Society for Microbiology. All rights reserved.
which can activate infected myeloid cells and inhibit
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Sia and Rengarajan
developed nearly a century ago, Mycobacterium bovis able to control infection in the form of LTBI, an esti-
bacillus Calmette-Guérin (BCG), an attenuated strain of mated 5 to 10% of people exposed to M. tuberculosis
M. bovis, remains the only licensed vaccine against TB. develop ATB, which is characterized by a persistent
Vaccination with BCG provides protection against se- cough accompanied by sputum production, weight loss,
vere forms of disseminated TB in children but has vari- weakness, and night sweats (9). Clinical diagnosis and
able efficacy in preventing pulmonary disease in children treatment of M. tuberculosis infection is complicated by
and adults (2–4). However, the immunological basis for a variety of coinfections and comorbidities.
the poor efficacy of BCG remains unclear. Moreover, Comorbidities that modulate immune function can
long-held concepts regarding the nature of desired im- exacerbate TB disease or contribute to progression of
mune responses in an ideal TB vaccine, namely, the in- individuals with LTBI to ATB. HIV coinfection in la-
duction of antigen-specific CD4 T cells producing IFN-γ, tently infected individuals increases the risk of develop-
are being updated to reflect the expanding knowledge ing TB from a 5 to 10% lifetime risk to a 10% annual
of host immunity to M. tuberculosis infection gathered risk, and HIV infection is the single greatest risk factor
from animal models and human cohort studies. Ad- for the development of TB (10–14). The relevance of
vances in imaging and single-cell technologies combined HIV coinfection to global TB mortality is highlighted by
with high-throughput approaches and systems-based the fact that more than a fifth of all TB-related deaths in
analyses are providing more information on the immune 2016 were in HIV-positive individuals (1). Progressive
response to M. tuberculosis infection at increasingly depletion and dysfunction of CD4 T cells following HIV
higher resolutions. As our understanding of the host reinfection leads to immune suppression and negatively
sponse to M. tuberculosis infection grows, opportunities impacts immunity to M. tuberculosis. Specific depletion
to leverage knowledge of the immunology of M. tuber- of M. tuberculosis-specific CD4 T cells has been reported
culosis infection toward improving therapeutics and in the peripheral blood (15, 16) and broncheoalveolar
vaccines for TB are increasing. lavage (BAL) samples (17, 18) of HIV-infected individ-
This article will cover integral features of the innate uals with LTBI. Several studies indicate that specific
and adaptive immune response to M. tuberculosis in- depletion may be a consequence of enhanced HIV co-
fection. Additionally, it will highlight recent findings on receptor expression in CD4 T cells, particularly CCR5,
the hallmark granuloma and novel cellular players con- in TB patients (15, 19–24). Alternative hypotheses to ex-
tributing to the host response to M. tuberculosis infec- plain specific depletion of M. tuberculosis-specific CD4
tion. Finally, it will provide an overview of the state of T cells include differential functionality of specific T
TB vaccine research, including a summary of BCG-based cells. In HIV coinfected LTBI, M. tuberculosis-specific
vaccines and the TB vaccine pipeline. CD4 T cells are reported to secrete interleukin 2 (IL-2) in
contrast to MIP-1β (macrophage inflammatory protein 1
beta) secreted by cytomegalovirus-specific CD4 T cells
IMMUNOPATHOGENESIS OF TB IN (16). Analysis of viral loads in HIV coinfected LTBI
HUMANS AND ANIMAL MODELS showed an inverse correlation between viral load and
Overview of Human TB the frequency of M. tuberculosis-specific CD4 T cells
Disease and Comorbidities secreting IL-2 (25), suggesting that IL-2 producing M.
Transmission of M. tuberculosis occurs after inhalation tuberculosis-specific CD4 T cells may be specifically
of aerosolized droplets containing live bacteria into the depleted in the context of HIV coinfection. Relatedly,
lungs. Successful transmission is influenced by a variety HIV-coinfected individuals have lower frequencies of
of conditions, including proximity and duration of cytokine-producing M. tuberculosis-specific CD4 T cells
contact with an individual with active TB (ATB) disease with impaired proliferative capacity compared to HIV-
and the immune-competency of the individual infected uninfected individuals with LTBI (26–28), suggesting
with M. tuberculosis (5–7). We now appreciate that in a M. tuberculosis-specific CD4 T-cell dysfunction during
clinical setting, M. tuberculosis infection presents as a HIV-infection. The relative contributions of depletion
continuum of diseased/infected states ranging from versus dysfunction of M. tuberculosis-specific CD4 T
asymptomatic latent TB infection (LTBI) to ATB disease. cells to enhanced TB risk following HIV infection remains
This complexity, combined with remarkable heteroge- unclear. Further, HIV infection may perturb protective
neity in lesions within a single patient, has presented immunity to M. tuberculosis in other immune compart-
unique challenges to the eradication of TB (8). While the ments, such as CD8 T cells. For instance, M. tuberculosis-
majority of individuals exposed to M. tuberculosis are specific CD8 T cells from individuals with LTBI are
2 ASMscience.org/MicrobiolSpectrum
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Immunology of M. tuberculosis Infections
reported to have impaired proliferation and degranulation Other animal models of M. tuberculosis infection in-
in HIV-infected compared to HIV-uninfected individuals clude guinea pigs, rabbits, fish, and non-human primates
(29). Studies have also described associations between TB (NHP). Each has distinct advantages and disadvantages
and many other conditions or activities, including smok- that make their use particularly suitable for different
ing, malnutrition, diabetes, helminth infections, chronic types of research questions. Following infection, guinea
lung diseases, and cancer (30, 31). Further investigations pigs exhibit pathological features, such as the organi-
will be required to fully understand the basis of identified zation and development of caseous necrotic granulomas,
associations with other infections and morbidities. that more accurately recapitulate the human granulo-
matous response compared to mice (41). Further, guinea
Animal Models of Infection pigs are very susceptible to M. tuberculosis infection and,
Knowledge of the host response to M. tuberculosis in- thus, are a good choice for testing candidate drugs and
fection has benefited greatly from the development vaccines and studying dissemination dynamics. Simi-
of animal models of infection. The variable outcomes larly, rabbits develop a well-organized granuloma that
of M. tuberculosis infection in humans are challenging can become necrotic following mycobacterial infection.
to model in a single animal model. Many experimen- However, rabbits are resistant to M. tuberculosis, and
tal animals are susceptible to M. tuberculosis infection high numbers of bacteria during inoculation or use of
and can inform us about aspects of human disease. The more virulent strains are needed (42–45). Nevertheless,
mouse model for TB benefits from many advantages: the rabbit model has been leveraged to study relatively
ease of manipulation and housing, availability of well- rarer forms of TB, such as cutaneous and meningeal
characterized inbred strains, sophisticated techniques TB (46, 47). The usefulness of both the guinea pig and
for the generation of mutant strains, availability of im- rabbit models is hampered by the scarcity of immuno-
munological and other reagents, and relatively low cost. logic reagents relative to mice. The zebrafish model has
Mice have been utilized to model host responses to provided novel insights into the establishment of the
M. tuberculosis infection, to evaluate drug and vaccine mycobacterial granuloma. Infection of transparent zeb-
candidates, and to study the immune response to mutant rafish larvae with the natural fish pathogen Mycobac-
strains of mycobacteria. Experimental infection can be terium marinum leads to the establishment of well-
delivered through multiple routes: intravenously, intra- organized granulomas that become necrotic and can
peritoneally, intratracheally, or via aerosolized particles. be visually monitored (48). The primary advantage of
The latter method, especially low-dose aerosol infection, the zebrafish model is the transparency of the zebra-
is the most physiologically relevant and has become the fish larvae, which, alongside facile manipulation of
preferred method. Different mouse strains have well- host and bacterial genetics, has been leveraged for in-
characterized lung pathologies and levels of suscepti- sight into early innate immune events leading to the
bility (32–36). Typically, following bacterial deposition formation of the granuloma as well as insights into
into the lungs, it takes approximately 2 weeks to begin human disease. Adaptive immunity is present in adult
priming adaptive immune responses in the lung-draining zebrafish, and different populations of CD4 T cells
lymph nodes and a further 1 to 2 weeks for robust par- have recently been described (49, 50), but these ani-
ticipation in the lungs by adaptive immune cells, but mals are no longer transparent, and relevance of the
bacterial burdens continue to be maintained at a high adult zebrafish immune response to human TB have yet
level in the lungs of M. tuberculosis-infected mice. There to be established.
are limitations to what can be gleaned from mouse The NHP model of M. tuberculosis infection reflects
models of M. tuberculosis infection due to the differences much of the heterogeneity observed in human TB. In-
in lung pathology between mice and humans. Further, fection of NHPs is typically performed by aerosol or
true latent infection and significant immune control of direct bronchoscopic deposition into the lungs of rhesus
infection are difficult to establish in the mouse model, or cynomolgus macaques and, depending on the dose of
though chemotherapeutically induced models of pauci- the inoculation and the strain of bacteria utilized, leads
bacillary disease in mice exist (37, 38). The development to symptomatic ATB disease or asymptomatic infection
of humanized mice that can recapitulate the heteroge- in which bacteria persist at low levels akin to LTBI. The
neity of human lung pathology may extend the advan- NHP model accurately recapitulates many of the hall-
tages of the mouse model, but humanized mice are also mark granulomas seen in humans, including the het-
reported to display aberrant T-cell responses and be erogeneity of granulomas that can be present in the same
unable to control bacterial burden (39, 40). animal (51), and presents clinical symptoms similar to
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Sia and Rengarajan
those seen in humans (52–57). The NHP model is (e.g., TLR-2, TLR-4, TLR-9) (72–74). Mannosylated
regarded as an important preclinical model for TB re- lipoarabinomannan, phosphatidyl-inositol mannosides,
search and is an excellent model for studying immunity phthiocerol dimycocerosates, phenolic glycolipids (PGLs),
to M. tuberculosis and assessing candidate drug and trehalose dimycolate, peptidoglycan, and other mycobac-
vaccine efficacies (58–63). Further, the NHP model can terial components are recognized by an array of cell sur-
be used to study reactivation in the setting of simian face and intracellular receptors that mediate phagocytosis
immunodeficiency virus coinfection or other types of and/or antimicrobial defenses. M. tuberculosis DNA (75,
immune modulation, such as anti-tumor necrosis-α 76) or bacterial second messengers (77) can be recognized
(anti-TNF-α) treatment, CD4 depletion, or inhibition of by cytosolic pattern recognition receptors (PRRs), such
indoleamine 2,3-dioxygenase (IDO) (64–71). as cGAS and STING (78, 79), to induce downstream
cytokine production and autophagy. Further, nucleotide
oligomerization domain-like receptors (NLRs) are cyto-
INNATE IMMUNITY TO solic PRRs that recognize M. tuberculosis pathogen-
M. TUBERCULOSIS INFECTION associated molecular patterns, such as muramyl dipep-
The earliest encounter between host and pathogen in TB tide, to activate a multiprotein complex termed the
occurs at the interface between innate immune cells and inflammasome. Functional redundancies for many of the
M. tuberculosis. While innate immunity is critical for receptors are likely to exist due to promiscuous ligand
early antimycobacterial responses, it is also important binding by different receptors and the wide array of
for the progression of infection and long-term control of available ligands on M. tuberculosis. Indeed, single or
M. tuberculosis by continually priming and educating double knockouts for canonical scavenger receptors and
adaptive immune responses and by regulating inflam- C-type lectin receptors did not modulate susceptibility or
mation. However, innate immune cells are often niches attenuate immune responses following M. tuberculosis
for bacterial replication, and M. tuberculosis utilizes infection (80). However, increased susceptibility to M.
a variety of strategies that subvert innate immune re- tuberculosis infection in a variety of knockout mice
sponses to establish a chronic infection. Here, we will demonstrate that a number of PRRs and their associated
detail key features of the innate immune response to signaling pathways also play important, nonredundant
M. tuberculosis infection, starting from recognition of roles in host defense against M. tuberculosis infection.
the bacterium and phagosomal defenses within infected M. tuberculosis expresses a variety of known or pu-
macrophages to priming of adaptive immune responses tative TLR ligands, and TLR-2, TLR-4, and TLR-9 have
by professional antigen-presenting cells. In between, we been implicated in host recognition of M. tuberculosis
will highlight how neutrophils and monocytes are mo- (reviewed in 73, 74). Polymorphisms in specific TLRs
bilized after M. tuberculosis infection, the role that or TLR signaling proteins have also been strongly as-
natural killer (NK) cells play during infection, how the sociated with pulmonary TB in humans and have been
balance of inflammation is regulated by the innate im- shown to influence immunity against M. tuberculosis
mune system, and how cell death affects the immune (81–84). The contribution of individual TLRs to im-
response. In each section, we will also highlight some munity against M. tuberculosis infection is variable, but
of the myriad strategies that M. tuberculosis utilizes to the importance of the TLR signaling pathway to anti-
subvert or evade the host innate immune response. mycobacterial immunity is evident in studies showing
that mice lacking the common TLR adaptor protein,
Recognition of M. tuberculosis by myeloid differentiation factor 88 (MyD88), quickly
Pattern Recognition Receptors succumb to M. tuberculosis infection (85, 86). Suscep-
Pathogen-associated molecular patterns on M. tubercu- tibility of MyD88–/– mice to M. tuberculosis infection
losis are recognized via a variety of receptors to medi- has been attributed to deficient expression of NOS2
ate opsonic and nonopsonic bacterial uptake: C-type (86), impaired ability to activate the IL-1β or IL-1 re-
lectins (e.g., mannose receptors, DC-SIGN, Dectin-1, ceptor (IL1R) pathway (87, 88), impaired receptivity
Dectin-2, Mincle), complement receptors (e.g., comple- of macrophages to IFN-γ signaling (89), and impaired
ment receptor 3), collectins (e.g., surfactant proteins A IL-12 and TNF-α responses in macrophages and den-
and D, mannose-binding lectin), scavenger receptors dritic cells (DCs) (85). Gene-deletion studies in single
(e.g., MARCO, SR-A1, CD36, SR-B1), Fc receptors (e.g., TLRs have revealed that innate immune responses to
FcgR), glycophosphatidylinositol-anchored membrane M. tuberculosis are likely the result of the complex ac-
receptors (e.g., CD14), and Toll-like receptors (TLRs) tivation of multiple signaling pathways. For instance,
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mice lacking both TLR-2 and TLR-9 are more suscep- controversial. Modulation of innate immune responses
tible to M. tuberculosis infection than mice lacking the by M. tuberculosis is also accomplished through the
ability to signal through either TLR by itself (90). The presence of immune-inhibitory lipid components that
susceptibility of MyD88–/– mice to M. tuberculosis in- compete with immune-activating mycobacterial compo-
fection is an example of the importance of common nents for the same receptors. For example, expression
adaptor molecules that integrate signals from multiple of tetraacylated sulfoglycolipids by the W-Beijing strain
PRRs and other innate immune pathways for the in- GC1237 can competitively bind TLR-2 to attenuate
duction of antimycobacterial immunity. Further evi- responses to canonical TLR-2 agonists, including my-
dence for this concept is demonstrated by the increased cobacterial lipomannans (104). Lastly, M. tuberculosis
susceptibility of M. tuberculosis-infected mice lacking can also impair innate immune responses to cell-
CARD9, an adapter molecule integrating signals from envelope components through enzymatic means. For
C-type lectin receptors, or PYCARD/ASC, an adapter instance, an M. tuberculosis serine-hydrolase, Hip1, was
molecule integrating signals from nucleotide oligomeri- found to cleave multimeric, cell wall-associated GroEL2
zation domain-like receptors for the induction of the to a secreted monomeric form to mediate attenuated
inflammasome (91, 92). macrophage and DC responses (105–109). Addition-
MyD88 signaling in innate immunity integrates sig- ally, M. tuberculosis mutants lacking hip1 or a putative
naling from TLR and IL-1 receptor families by bridging mycobacterial metalloprotease, zmp1, display enhanced
ligand-receptor binding to IL-1-receptor-associated kinases inflammasome activation (106, 110), suggesting that
and the activation of multiple downstream pathways, in- M. tuberculosis has multiple strategies for dampening
cluding NF-κB, mitogen-activated protein kinases, and activation of the inflammasome.
activator protein 1. The IL-1 signaling pathway is clearly Thus, in addition to the array of host receptors that
required for resistance to M. tuberculosis infection in mediate recognition of M. tuberculosis, innate immune
mouse models and is supported by human immunogenetics responses to infection likely depend on the strain of
studies (93–96). In mice, the absence of IL-1 signaling led M. tuberculosis, the presence of cell wall components
to severe susceptibility to M. tuberculosis infection. Both that can competitively inhibit the activation of PRRs,
IL-1α and IL-1β, as well as their common receptor, IL-1R1, and the presence of M. tuberculosis enzymes that modify
have been implicated in immunity to M. tuberculosis (87, the immunogenicity of cell envelope components.
88, 97–101). Secretion of the mature form of IL-1β requires
cleavage by the terminal inflammasome effector, caspase-1, Phagosomal Defense in Macrophages
but M. tuberculosis-infected mice lacking MyD88, ASC, or Macrophages are the first immune cells to encounter
caspase-1 signaling do not display impaired IL-1β levels M. tuberculosis during infection and also represent the
(87). Further, mice deficient in IL-1β are considerably more primary replicative niche for M. tuberculosis. Recognition
susceptible to M. tuberculosis infection than mice lacking of M. tuberculosis by macrophages leads to phagocytosis
ASC or caspase-1 (87). These findings suggest that IL-1β is and sequestration of the bacterium in phagosomes, which
a key mediator of resistance to M. tuberculosis infection typically eradicate pathogens via fusion with lysosomes
but also indicate that the basis for resistance conferred by and consequent acidification of the pathogen-containing
MyD88, CARD9, and PYCARD/ASC likely depend on phagolysosome. However, M. tuberculosis is able to sur-
additional factors beyond IL-1β. vive and replicate in the phagosome by inhibiting phago-
While host recognition of M. tuberculosis leads to the somal maturation and phagolysosomal generation through
activation of innate immunity, M. tuberculosis has also a variety of mechanisms (reviewed in 72, 111). Further,
evolved strategies that evade innate immune responses transcriptional profiling of intraphagosomal bacteria indi-
mediated by PRRs. Strain-specific expression of cell en- cated that M. tuberculosis readily counters the nitrosative,
velope components may be associated with differential oxidative, hypoxic, and nutrient-poor phagosomal envi-
immune responses. For example, the W-Beijing lineage ronment through the expression of stress-adaptive genes
strain, HN878, has been found to express polyketide (112), though a genome-wide transposon site hybridiza-
synthase-derived phenolic glycolipids that are missing tion screen for M. tuberculosis survival in macrophages
in lab-adapted H37Rv or other clinical isolates (i.e., suggested that M. tuberculosis constitutively expresses
CDC1551) (102). Expression of PGL by HN878 has genes required for its survival (113). Nevertheless, it is clear
been found to diminish production of multiple innate that M. tuberculosis has adapted for a lifestyle inside the
immune cytokines and chemokines (102, 103), though macrophage and employs many strategies to survive within
its role in the increased virulence of HN878 remains these cells.
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Sia and Rengarajan
M. tuberculosis glycolipids can prevent accumulation complement receptor 3 depended on host cholesterol,
of phosphatidylinositol 3-phosphate on phagosomal which mediated phagosomal association with coronin-1
membranes and prevent phagolysosome biosynthesis and consequent inhibition of phagolysosome forma-
(114). M. tuberculosis also secretes phosphatases (SapM tion through activation of host calcineurin (138, 139).
and PtpA) and serine/threonine kinases (PknG) that Alternatively, TLR-2 recognition of mycobacterial
are proposed to interfere with phagosomal maturation mannosylated lipoarabinomannan activates NF-κB and
(115–121). There is also evidence that M. tuberculosis NOS2 gene transcription that leads to antimycobacterial
lipids, in particular, phthiocerol dimycocerosates, can nitric oxide (NO) production (140). NO production is
mediate escape from the phagosome and host cell death strongly associated with resistance to M. tuberculosis,
(122). An M. tuberculosis secretion system, ESX-1, is though evidence for the antimycobacterial effects of
also known for mediating disruptions in phagosomal NO is stronger in the mouse model. In mice, reactive
integrity and preventing phagosome maturation. Pro- nitrogen intermediates are toxic to mycobacteria in vitro
motion of aberrant phagosomal integrity and bacterial (141–143), and infection can be exacerbated by the
replication by M. tuberculosis ESX-1 is countered by inhibition of NOS in vitro (144, 145) or in vivo (146–
IFN-γ-induced, Rab20-mediated phagosomal matura- 148). NO production following IFN-γ signaling has also
tion (123). ESX-1-mediated phagosomal escape of bac- been reported to limit overt inflammation by inhibiting
teria is hypothesized to work through disruption of the processing of IL-1β by the inflammasome (149). Re-
phagosome by the 6-kDa early secretory antigenic target latedly, mice with disrupted NOS2 alleles display exa-
(ESAT-6) (124–127), though recent evidence proposes cerbated disease following M. tuberculosis infection
a contact-dependent, ESAT-6-independent mechanism (146, 150). Although in vitro studies using human al-
for ESX-1-mediated phagosomal permeabilization (128). veolar macrophages and primary monocytes did not find
Nevertheless, ESX-1-mediated permeabilization of the an antimycobacterial role for NO (151–153), specific
phagosome exposes M. tuberculosis pathogen-associated staining for NOS2 in the BAL of TB patients reveals
molecular patterns, such as N-glycolyl-muramyl dipep- upregulation in infected individuals compared to healthy
tide, to cytoplasmic nucleotide oligomerization domain controls (154). Nevertheless, M. tuberculosis has several
2 receptors to induce type I IFNs (129, 130). ESX-1- strategies to cope with otherwise damaging reactive ni-
mediated permeabilization of the phagosome also exposes trogen and oxygen intermediates: M. tuberculosis KatG,
extracellular bacterial DNA to the cytosolic DNA-sensing a catalase-peroxidase, can inactivate phagosomal reac-
pathway, which leads to targeting of M. tuberculosis to tive oxygen (155), and the M. tuberculosis proteasome
autophagosomes for subsequent killing (75). M. tuber- can mediate resistance to nitrosative stresses (156). Pro-
culosis ESX-3 has also been implicated in modulating miscuous recognition of mycobacterial antigens by the
intracellular trafficking of bacteria to avoid phagosomal same receptor may also have convergent outcomes as in
maturation through inhibition of the host endosomal the case for TLR-2-mediated recognition of M. tuber-
sorting complex required for transport (131–133). Thus, culosis cell wall fractions leading to TNF-α production
studies of the M. tuberculosis ESX secretion system have in murine macrophages (157). TLR-mediated recogni-
provided evidence for its role in both bacterial evasion tion of M. tuberculosis is also reported to synergize
of phagosomal pressures and host sensing of bacterial with the vitamin D pathway to induce the antimicrobial
components. In addition to the ESX system, M. tubercu- peptide (AMP), cathelicidin, in human macrophages
losis also expresses two SecA ATPase protein homologues (158, 159). The biologically active vitamin D metabolite,
(SecA1 and SecA2) involved in protein export (134). calcitriol, induces hCAP-18, a gene encoding the pro-
SecA2, in particular, has been implicated in virulence and form of cathelicidin, following TLR ligation of macro-
intracellular growth (135, 136). Interestingly, both M. tu- phages (158–160). In addition to direct antimicrobial
berculosis and BCG ΔsecA2 mutants are enriched in acidi- activity, cathelicidin has been shown to exert antimi-
fied phagosomes, indicating that mycobacterial SecA2 is crobial functions by activating transcription of host
required for arrest of phagosome maturation (137). autophagy genes Beclin-1 and Atg5 (161). The vitamin
M. tuberculosis entry into macrophages through dif- D pathway also synergizes with IFN-γ secreted by T cells
ferent receptors can lead to distinct activation of path- to induce IL-15 autocrine signaling to promote auto-
ways that can inhibit or promote bacterial replication. phagy and phagosomal maturation in M. tuberculosis-
The overall effect of multiple receptors engaging distinct infected human macrophages (162).
or overlapping M. tuberculosis ligands is a complex and Autophagy is the process whereby cytoplasmic con-
dynamic issue. For example, M. tuberculosis uptake by stituents are degraded or recycled. A role for autophagy
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in antimycobacterial immunity in macrophages has of Atg5, but not other autophagy genes, compromised
been extensively characterized. Initial studies utilizing control of M. tuberculosis (172, 173). Deletion of the
M. bovis suggested that autophagy plays a role in pro- autophagy-related genes Ulk1, Ulk2, Atg4B, or p62
moting phagosomal maturation to enhance bacterial compromised the ability to induce autophagy, but they
killing (163). Moreover, LRG-47, an IFN-γ inducible were dispensable for the control of M. tuberculosis
p47 GTPase reported to be critical for phagosomal (173). Analysis of lung sections from M. tuberculosis-
maturation and control of M. tuberculosis (164), is also infected Atg5 knockout mice indicated that Atg5 may be
involved in the induction of autophagy in M. bovis- involved in regulation of neutrophil responses during
infected macrophages (165). Autophagy-related genes infection, suggesting autophagy-independent roles for
were revealed to be involved in regulating the intracel- Atg5. Further, a recently described role for Atg5 in LC3-
lular bacterial load of lab-adapted and clinical isolates associated phagocytosis during M. tuberculosis infection
of M. tuberculosis in a genome-wide small interfering supports the notion that specific components of auto-
RNA screen in infected human macrophage-like THP-1 phagy can also overlap with other phagosomal path-
cells (166). Accumulating evidence indicates that auto- ways in immunity against mycobacteria (174).
phagy is integrated into the host response to M. tuber- Taken together, it is clear that macrophage recogni-
culosis infection by synergizing with pathogen sensing, tion and phagocytosis of M. tuberculosis lead to a dy-
phagosomal maturation, and IFN-γ inducible path- namic tug of war between antimycobacterial defenses
ways to mediate antimycobacterial immunity: STING- and M. tuberculosis immune evasion. Macrophage
dependent cytosolic sensing of M. tuberculosis DNA defenses include AMPs, nitrosative stresses, phagolyso-
is required to deliver bacteria to autophagosomes and somal fusion, and autophagy and may operate inde-
restrict bacterial replication (75); knockdown of cGAS pendently of or subsequent to IFN-γ signaling. On the
in infected macrophages attenuated the induction of other hand, M. tuberculosis can subvert macrophage
autophagy and survival during chronic M. tuberculosis defenses at the level of the bacterial cell wall components
infection (78); detection of cyclic-di-AMP secreted by that limit phagosomal maturation and the bacterial
M. tuberculosis in macrophages induced type I IFN pro- genes that combat or allow adaptation to intracellular
duction and autophagy to limit bacterial virulence (77); immune pressure.
PARKIN, a conserved ubiquitin ligase, was shown to
ubiquitinate M. tuberculosis-containing phagosomes to Recruitment and Function of Neutrophils and
facilitate ubiquitin-mediated autophagy and restrict bac- Monocytes Following M. tuberculosis Infection
terial replication (167); IFN-γ-induced host ubiquilin-1 Secretion of cytokines and chemokines early during
colocalizes with M. tuberculosis and mediates trafficking infection recruits additional phagocytes to the site of
of bacteria to autophagosomes (168); IFN-γ receptor infection. Early secretion of chemoattractants may be
signaling mediated by the MyD88 adaptor-like (Mal) attributed to infected alveolar macrophages as well as
molecule induced autophagy and killing of intracellular lung epithelial cells (175–177). Moreover, a recent study
M. tuberculosis in macrophages (169). Several studies suggests that cross talk between primary bronchial epi-
have also delineated strategies employed by M. tuber- thelial cells and infected macrophages may also promote
culosis to evade autophagy. M. tuberculosis is reported secretion of chemokines (178). Trafficking of additional
to induce the expression of microRNA-33 to inhibit monocytes and granulocytes to the lung exerts immune
autophagy and regulate intracellular lipid metabolism pressure on M. tuberculosis and is crucial for the initi-
to benefit bacterial replication (170). Further, a screen of ation of adaptive immune responses, but it may also
M. tuberculosis cosmid clones in search of genes that promote M. tuberculosis cell-to-cell transmission and
inhibited bone marrow-derived DC antigen presentation dissemination.
revealed M. tuberculosis PE_PGRS47 (Rv2741) as an Recruitment of neutrophils serves as an early line of
inhibitor of autophagy-mediated antigen presentation defense against M. tuberculosis infection via secretion
(171), suggesting that M. tuberculosis-mediated im- of antimicrobial molecules and inflammatory media-
pairment of innate immunity can also negatively impact tors, but neutrophils also serve as niches for bacterial
the generation of adaptive immunity. It is also becoming replication and can impede immunity against M. tuber-
clear that autophagy-related proteins are likely to per- culosis. In humans with active pulmonary TB, neutro-
form multiple functions, and care must be taken when phils have been found to be a significant population
interpreting specific knockouts or knockdowns of indi- of M. tuberculosis-infected phagocytes in the BAL and
vidual genes. For instance, myeloid cell-specific ablation sputum (179). Whole blood transcriptional profiling
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Sia and Rengarajan
also identified a neutrophil signature in ATB patients therapy (191). Further, as discussed later in the chapter,
that is associated with type I and type II IFN-inducible dysregulation of neutrophil recruitment by unrestrained
genes (180) and expression of the inhibitory molecule IL-17 responses during M. tuberculosis infection can in-
PD-L1 (181), suggesting that neutrophils may play an cur pathological consequences by driving lung-damaging
immunomodulatory role in human TB. In mice, the ki- inflammation. Thus, the overall effect of neutrophil re-
netics and magnitude of neutrophil recruitment follow- cruitment to the site of M. tuberculosis infection may be
ing M. tuberculosis infection depends on the strain of determined by host genetics, the context of infection
mouse infected. Evidence for a pathogenic role for neu- (pulmonary versus extrapulmonary), or timing and du-
trophils is shown in studies comparing neutrophil re- ration of neutrophil activity.
cruitment in resistant versus susceptible mouse strains In addition to neutrophils, monocytes are recruited to
(182, 183). When comparing resistant C57BL/6 mice to the site of M. tuberculosis infection. Similar to neutro-
susceptible DBA/2 mice after M. tuberculosis infection, phils, monocyte recruitment is important for innate im-
a study found that neutrophils were rapidly recruited munity during M. tuberculosis infection but may also
into the broncheoalveolar space at higher magnitudes inadvertently promote M. tuberculosis dissemination.
in susceptible mice. Depletion of neutrophils at the onset C-C chemokine receptor type 2 (CCR2) is a chemokine
of M. tuberculosis infection specifically extended the life receptor expressed on monocytes and is responsible for
spans of DBA/2 mice, suggesting that early neutrophil CCL2-mediated recruitment of monocytes to sites of
involvement was pathogenic in genetically susceptible bacterial infection (192). CCR2 was found to mediate
mice (183). Similarly, neutrophil depletion in susceptible immunity against M. tuberculosis depending on the dose
I/St mice shortly after M. tuberculosis infection reduced of infection. CCR2 knockout mice were more suscepti-
lung pathology and bacterial growth and improved ble to high-dose intravenous M. tuberculosis infection
survival compared to C57BL/6 mice (184). In a separate (193), but not after low-dose infection (194). Monocytes
study, depletion of neutrophils 5 weeks after aerosol have been shown to differentiate into macrophages and
M. tuberculosis infection of resistant BALB/c mice en- DCs following M. tuberculosis infection, and monocytes
hanced the levels of lung IL-6 and IL-17 without im- transferred into M. tuberculosis-infected mice were shown
pacting IFN-γ and modestly enhanced control of bacterial to be the predominant population of innate immune cells
burden (185). Neutrophil depletion in the first 4 days producing iNOS (195). Additionally, monocyte delivery
following intravenous M. tuberculosis infection of BALB/ of M. tuberculosis to pulmonary lymph nodes can coor-
c mice, however, led to enhanced bacterial growth at dinate with DCs to prime CD4 T cells after infection (196).
extrapulmonary sites, suggesting that antimycobacterial Monocytes may therefore represent a recruited popula-
immunity conferred by neutrophils may be dependent on tion of innate cells that combat M. tuberculosis infection
the route of infection and the kinetics of neutrophil in- through the production of reactive nitrogen intermediates
volvement (186). Utilizing fluorescently labeled bacteria, and priming of adaptive immunity. However, monocyte
a recent study demonstrated that bacterial distribution in recruitment following M. tuberculosis infection may also
myeloid cells shifts from CD11b+Ly6G– monocytes and be detrimental to the host by providing an environment
macrophages to CD11b+Ly6G+ neutrophils in Nos2–/– full of permissive cells. Treatment of M. tuberculosis-
animals infected with M. tuberculosis, suggesting that infected mice with polyinosinic-polycytidylic acid (polyIC)
neutrophil influx can create a growth-permissive envi- led to CCR2-dependent recruitment of a population of
ronment for M. tuberculosis under NO-deficient condi- M. tuberculosis-permissive monocytes, severe susceptibil-
tions (187). Evidence for beneficial roles that neutrophils ity, and early mortality (197). Interestingly, susceptibility
play in antimycobacterial defense focus on neutrophil of polyIC-treated mice to M. tuberculosis infection was
secretion of AMPs such as cathelicidin and lipocalin-2 to dependent on type I IFN signaling and was not due to any
restrict bacterial replication (188) or via uptake of AMP- particular alteration to the T-cell response. The recruit-
containing apoptotic neutrophils by M. tuberculosis- ment of neutrophils and monocytes to the site of M. tu-
infected macrophages (189). Neutrophils can also release berculosis infection represents a host strategy to contain
chromatin scaffolds that trap extracellular bacteria in an bacterial replication that is co-opted by the bacterium to
AMP-containing mesh. M. tuberculosis has been shown facilitate its growth and dissemination.
to induce the formation of neutrophil extracellular traps
in vitro (190), and levels of neutrophil extracellular traps NK Cells in M. tuberculosis Infection
detected in the plasma of ATB patients were associ- NK cells are innate lymphocytes with the capacity to
ated with disease severity and decreased with antibiotic secrete IFN-γ and perform cytolytic functions to mediate
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control of a variety of pathogens, including M. tuber- In addition to induction of type I IFNs, neutrophils have
culosis. Various components of the M. tuberculosis cell also been reported to drive lung destruction through the
wall can bind directly to NKp44 found on NK cells (198), secretion of matrix metalloproteinase 8 (216). The ma-
and NK cells can also recognize stress molecules upregu- trix metalloproteinase family of enzymes has been im-
lated on the surface of M. tuberculosis-infected cells (199). plicated in lung tissue destruction during M. tuberculosis
NK cells can mediate direct killing of M. tuberculosis- infection (217–220) but has also been shown to promote
infected macrophages (199) but can also restrict intramacrophage recruitment and bacterial dissemination
cellular bacterial replication via secretion of IL-22 (200) during infection of zebrafish (221).
and IFN-γ (201) to increase phagolysosomal fusion of Eicosanoids are lipid mediators of inflammation de-
M. tuberculosis-containing phagosomes. Additionally, rived from the oxidation of arachidonic acid. The bal-
NK cells can enhance immunity against M. tuberculosis ance between proinflammatory prostaglandin E2 (PGE2)
indirectly by enhancing CD8 T-cell production of IFN-γ and anti-inflammatory lipoxin A4 (LXA4), two members
(202) by promoting the expansion of γδ T cells (203) and of the eicosanoid family of signaling molecules, can de-
by lysing M. tuberculosis-expanded regulatory T cells termine the outcome of M. tuberculosis infection (222–
(204). The cytolytic capacity of NK cells is diminished 224). During M. tuberculosis infection, mice incapable
in ATB patients relative to healthy controls and can be of synthesizing PGE2 display increased susceptibility
reconstituted following antibiotic therapy (205). Further, (223), and absence of the enzyme 5-lipoxygenase, which
NK cell function in TB patients can be attenuated by metabolizes arachidonic acid to LXA4, confers resistance
monocyte-derived IL-10 (201). Interestingly, a popula- (222). Importantly, therapeutic correction of low PGE2
tion of IL-21-dependent NK cells that appears following levels can confer enhanced survival in highly susceptible
BCG vaccination has been shown to expand following mice infected with M. tuberculosis (100). Leukotriene
M. tuberculosis challenge (206), suggesting that NK cells A4 hydrolase is an enzyme that catalyzes the production
may also display some hallmark characteristics of mem- of proinflammatory leukotriene B4 from leukotriene A4,
ory cells. which can also be converted to anti-inflammatory LXA4
as a counterbalance. In zebrafish, LTA4H mutants were
Inflammation and Cell Death found to be hypersusceptible to M. marinum infection
During M. tuberculosis Infection due to dysregulation of the balance between leukotrienes
The regulation of inflammation is a critical factor that and lipoxins; increased levels of LXA4 in LTA4H mu-
determines the outcome of M. tuberculosis infection. tants impaired TNF-α responses and promoted sus-
Overexuberant inflammation impairs cellular immunity, ceptibility (225). The relevance of this finding to humans
damages lung tissue, and can lead to lung cavitation and is highlighted in a TB meningitis cohort in Vietnam
enhanced transmission. Inversely, too little inflamma- where heterozygosity for six LTA4H polymorphisms
tion can impair control of bacterial burden by delaying conferred a survival advantage over homozygosity (225).
the induction of innate and adaptive immunity. While Indeed, anti-inflammatory glucocorticoid treatment effi-
neutrophil recruitment and activity during M. tubercu- cacy in TB meningitis patients can be differentiated by
losis infection can help contain bacterial replication, a single nucleotide polymorphism in the LTA4H pro-
sustained neutrophilic inflammation can mediate dam- moter controlling transcriptional activity, which suggests
aging inflammation and promote disease. Importantly, that the balance of inflammation is critical to disease
whole blood transcriptomics identified a neutrophil- progression and treatment outcomes in TB meningitis
driven type I IFN-inducible signature in human TB that (226).
decreased upon treatment (180). Excessive type I IFN TNF-α is a critical proinflammatory cytokine in im-
signaling has been shown to promote disease in mouse munity against M. tuberculosis infection and can be se-
models and human samples. Mice lacking type I IFN creted by a number of innate and adaptive immune cells.
signaling are more resistant to M. tuberculosis infection The importance of TNF-α in antimycobacterial immu-
(207–210), though signaling through type I IFNs may nity is clearly demonstrated by heightened susceptibil-
play a protective role in the absence of IFN-γ (211, 212). ity of TNF-α antibody-depleted animals or in animals
Mechanisms underlying the pathogenic role of type I lacking TNF receptor signaling following M. tubercu-
IFNs during M. tuberculosis infection include inhibition losis infection (227). TNF-α is also a critical mediator of
of IL-1β production (213, 214), induction of IL-10 to immunity against TB in humans. This is demonstrated
impair innate cytokine production (215), and loss of by increased rates of progression to ATB in LTBI pa-
IFN-γ responsiveness in infected macrophages (215). tients receiving anti-TNF treatment for inflammatory
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disorders (228), which can be recapitulated in the NHP lowing low-dose aerosol infection with virulent M. tuber-
model of infection (70). The effects of anti-TNF treat- culosis (223). Host cell necrosis following M. tuberculosis
ment in humans and NHPs, as well as in mice (229– infection can be induced through activation of the cyto-
231), suggests that TNF-α is critical for maintaining solic receptor interacting protein kinase 3 pathway, which
sequestration of M. tuberculosis in the granuloma. inhibits apoptosis of infected macrophages through Bcl-
Histopathological evidence from gene-disrupted or xL and promotes necrosis through upregulation of ROS
antibody-depleted mice infected with M. tuberculosis (242). Additionally, macrophages infected with virulent
also suggests that TNF-α signaling may be playing a H37Rv, but not avirulent H37Ra, undergo proteolysis
role in modulating apoptotic or necrotic cell death at the N-terminal of annexin-1, which prevents the com-
following infection (229, 231). pletion of the apoptotic envelope and drives macrophage
Cell death can be a means of restricting bacterial re- necrosis (235). Taken together, apoptosis represents a
plication by the host or a way to disseminate to second- strategy by the host to limit infection through the com-
ary loci of infection for M. tuberculosis. Apoptosis of bination of bacterial sequestration in apoptotic vesicles
M. tuberculosis-infected cells leads to fewer viable bac- and the induction of adaptive immune responses, but
teria and effective cross-presentation of bacterial antigens M. tuberculosis may delay apoptosis or promote necrosis
(224, 232, 233), whereas necrosis of M. tuberculosis- to facilitate replication and dissemination.
infected cells allows viable bacteria to exit and disseminate
(223, 234, 235). Proapoptotic M. tuberculosis mutants Initiation of Adaptive Immunity
lacking secA2 (236) and nuoG (237) were attenuated to M. tuberculosis by DCs
in vivo, and mice infected with these strains displayed An important function of innate immunity during M.
enhanced priming of adaptive immunity compared to in- tuberculosis infection is the priming of adaptive immune
fection with wild-type M. tuberculosis, suggesting that responses. DCs are professional antigen-presenting cells
prevention of host cell apoptosis is an M. tuberculosis vir- that initiate adaptive immunity by presenting M. tuber-
ulence strategy. Relatedly, M. tuberculosis-infected mu- culosis antigens in the context of major histocompati-
rine neutrophils can aid in DC trafficking to the draining bility complex (MHC), costimulatory molecules, and
lymph nodes to initiate antigen-specific CD4 T-cell re- cytokines. Depletion of cells expressing the pan-DC
sponses (238), but M. tuberculosis delays CD4 T-cell marker, CD11c, following M. tuberculosis infection
priming by inhibiting neutrophil apoptosis (239). Infec- impaired control of bacterial burden and delayed the
tion with the proapoptotic nuoG mutant M. tuberculosis initiation of adaptive immunity, illustrating the impor-
resulted in earlier DC trafficking to lung-draining lymph tance of DCs in mobilizing adaptive immune responses
nodes and earlier priming of antigen-specific CD4 T cells, that can control bacterial replication (243). There is
but enhanced priming was abrogated upon neutrophil abundant evidence that M. tuberculosis is able to infect
depletion (239). Additionally, uninfected macrophages murine (244–246) and human DCs (247–249). In mice
performing a constitutive housekeeping function called infected with green fluorescent protein GFP-expressing
efferocytosis can uptake M. tuberculosis-containing apo- M. tuberculosis, DCs were found to be the major pop-
ptotic bodies, which leads to delivery and killing of bac- ulation of phagocytes infected by bacteria after 4 weeks
teria in lysosomes (240). This suggests that apoptosis may (246). Upon M. tuberculosis infection, DCs mature and
be a host strategy to limit bacterial replication by se- migrate to the lung-draining lymph nodes to initiate
questering bacteria in vesicles that can be safely degraded antigen-specific T-cell responses, which depended on
by nearby innate immune cells. Inhibition of apoptosis the chemokine receptor CCR7 and its corresponding
by M. tuberculosis is driven by host intrinsic factors fol- chemokines CCL19 and CCL21 (250–252). Further, IL-
lowing infection with virulent strains. The proinflamma- 12, a cytokine secreted by myeloid cells and important for
tory eicosanoid PGE2 has been demonstrated to regulate the induction of IFN-γ responses, is required for DC mi-
synaptotagmin-7, a calcium sensor that maintains plasma gration during M. tuberculosis infection (253). Priming of
membrane integrity (241). Human macrophages infected adaptive immune responses requires the transport of live
with virulent M. tuberculosis H37Rv, but not avirulent bacteria to the lung-draining lymph nodes (246, 250), but
H37Ra, promote LXA4 production and inhibition of antigen-specific T cells can be primed by both the infected
PGE2 biosynthesis, which impairs resealing of plasma migratory DC and uninfected lymph node resident DC. A
membrane disruptions to preferentially induce host cell study demonstrated that infected DCs migrate to the
necrosis instead of apoptosis (241). Mice lacking PGE2 lung-draining lymph nodes, where they secrete soluble,
also suffered from increased lung bacterial burden fol- unprocessed M. tuberculosis antigens that are summarily
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phagocytosed by uninfected lymph node resident DCs M. tuberculosis subversion of DC functions can interfere
(254). The exportation of M. tuberculosis antigens was with antigen presentation and delay or impair the initi-
initially proposed to benefit the host by circumventing ation of the adaptive immune response. Improving DC
inefficient antigen presentation by infected DCs. How- functions during M. tuberculosis infection may improve
ever, secretion of M. tuberculosis antigens by infected innate and adaptive immunity and enhance immune
DCs may also benefit the pathogen by diverting antigen control of bacterial burden. A study that exoge-
away from MHC class II antigen presentation (255). nously engaged the CD40 costimulation pathway in
Effective interaction between DCs and T cells is de- M. tuberculosis-infected DCs improved DC functions
pendent on appropriate function of antigen presentation and promoted antigen-specific CD4 T-cell responses that
machinery, including expression of MHC, costimula- augmented control of lung bacterial burden (268). Fur-
tory molecules, and cytokines following M. tuberculosis ther, mucosal transfer of Ag85B-loaded DCs following
infection. However, there is abundant evidence that challenge with M. tuberculosis augmented the efficacy of
M. tuberculosis infection impairs antigen presentation BCG vaccination (269), suggesting that early antigen
to evade antigen-specific T-cell responses. It is well rec- presentation by DCs is an important component that
ognized that M. tuberculosis infection leads to impaired determines the efficacy of vaccine-induced immunity.
MHC class II antigen presentation by macrophages DCs are critical players that initiate adaptive immune
(reviewed in 256). M. tuberculosis-mediated inhibition responses to M. tuberculosis and determine the outcome
of phagosomal maturation has been implicated in at- of infection. Interventions or therapies that improve DC
tenuating processing of M. tuberculosis antigen 85 functions may provide benefits by augmenting cross talk
(Ag85) and the MHC class II-associated invariant chain between DCs and antigen-specific T cells.
(257). Multiple studies have also reported that M. tu-
berculosis infection impairs MHC class II expression
in macrophages through inhibition of class II transacti- ADAPTIVE IMMUNITY AGAINST
vator, a master transcriptional regulator controlling M. TUBERCULOSIS
expression of MHC class II molecules (258–261), al- Protective immunity to M. tuberculosis and control
though there is little evidence of similar inhibition of bacterial replication requires adaptive immune re-
of MHC class II in DCs. Nevertheless, M. tuberculosis sponses. This is best exemplified by the extreme sus-
infection of DCs leads to functional impairment of an- ceptibility to mycobacterial infections of lymphopenic
tigen presentation. M. tuberculosis infection has been HIV patients and gene-deleted mice lacking MHC
shown to impair DC maturation of human (reviewed class II or T cells in general. Cytokine secretion and di-
in 262) and murine DC functions (reviewed in 263, rect antimicrobial actions of antigen-specific T cells are
264). Studies examining proliferation of T-cell recep- key features of the adaptive immune response against
tor transgenic CD4 T cells specific for M. tuberculosis M. tuberculosis infection. Further, the long-lived nature
Ag85 as a proxy for functional antigen presentation of antigen-specific memory T cells provides the basis for
have demonstrated that M. tuberculosis EsxH can im- developing vaccines that induce antimycobacterial im-
pair antigen processing through inhibition of the host munity. There are also expanding roles for B cells, γδ
endosomal sorting complex required for transport T cells, and CD1-restricted T cells that provide specific
(ESCRT) (265). Additionally, M. tuberculosis promotes responses to a diverse set of M. tuberculosis antigens
suboptimal antigen presentation in vitro and in vivo that complement antigens classically presented through
without detectable differences in the expression levels MHC class I and II. However, adaptive immune re-
of costimulatory molecules when compared to BCG- sponses can also become malignant by promoting ex-
infected DCs (266). Interestingly, studies using a mutant cessive inflammation or be rendered ineffective from
M. tuberculosis strain lacking hip1 (discussed above) chronic antigen exposure. Here, we cover the impor-
indicate that M. tuberculosis readily impairs DC costi- tance of timing, location, and quality of CD4 T-cell
mulation and cytokine production to evade antigen- responses during M. tuberculosis infection, how CD8
specific CD4 T-cell responses (107, 109), and a recent T cells contribute to immunity against M. tuberculosis,
study demonstrated that BCG hip1 retains similar im- the roles that inhibitory receptors play during infection,
mune evasion functions (267). Taken together, the ini- the phenotypes and functions of memory T cells, and the
tiation of the adaptive immune response requires the roles that B cells, γδ T cells, CD1-restricted lymphocytes,
participation of DCs, which themselves are readily and mucosal associated invariant T (MAIT) cells play in
infected and subverted by M. tuberculosis infection. immunity against M. tuberculosis.
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Sia and Rengarajan
Kinetics and Homing of CD4 T Cells to vasculature-restricted CD4 T cells that expressed
after M. tuberculosis Infection CX3CR1 (280). Interestingly, cells retained in the lung
In the mouse model of infection, CD4 T-cell responses vasculature secreted the highest amount of IFN-γ during
are absolutely required to control bacterial replication, infection (280). Adoptive transfer studies demonstrated
and animals lacking such responses succumb rapidly that IFN-γ accounted for greater control of bacterial
(270, 271). MHC class II knockout mice or CD4 de- burden in the spleen over the lung and drove immuno-
pletion led to abrupt mortality following M. tuberculosis pathology when overexpressed (281), suggesting that
infection (270, 271). CD8 T cells play a key role in im- the function of IFN-γ may be to mediate control of bac-
munity against M. tuberculosis but cannot compensate terial dissemination to extrapulmonary sites and that
for CD4 deficiency (270). Similarly, antibody depletion IFN-γ may be detrimental when unrestrained. The dis-
of CD4 in cynomolgus macaques severely compromised tinction between vasculature-restricted and parenchyma-
control of M. tuberculosis and led to reactivation in la- localizing CD4 T cells seems less important in rhesus
tently infected animals (69). Thus, the initiation of the macaques (282), where the majority of antigen-specific
CD4 T-cell response is a key feature defining the out- CD4 T cells can be found in the lung parenchyma but are
come of M. tuberculosis infection. There is a widely re- restricted to the outer lymphocytic cuff of granulomas.
cognized delay in the initiation of antigen-specific CD4 Notably, studies have demonstrated that expression
T-cell responses following low-dose aerosol infection of of IDO by cells in the granulomas of M. tuberculosis-
mice (250, 272–275) and NHPs (276). M. tuberculosis- infected rhesus macaques can mediate inhibition of T cell
infected cynomolgus macaques had detectable antigen- entrance into granuloma, and biochemical inhibition
specific responses 4 weeks postinfection (276). In mouse of IDO led to reorganization of the granuloma to include
models of infection, antigen-specific CD4 T-cell re- T cells localizing into the macrophage core (66, 283).
sponses are first detected in the lung-draining lymph Taken together, there is strong evidence that localization
nodes 2 weeks after infection. Significant antigen-specific of antigen-specific CD4 T cells into the lung tissues where
lung CD4 T-cell responses are subsequently detected in M. tuberculosis-infected myeloid cells reside is an impor-
the lungs 3 weeks after infection. This is in stark contrast tant feature of protective immunity to M. tuberculosis.
to antigen-specific responses to other bacterial (277) or
viral (278) pathogens, which are detected swiftly after Quality and Specificity of the CD4
infection. Adoptive transfer of ESAT-6-specific CD4 T-Cell Response to M. tuberculosis
T cells prior to aerosol M. tuberculosis infection have The quality of the T-cell response is an important feature
demonstrated an apparent kinetic bottleneck whereby determining the outcome of M. tuberculosis infection.
lung antigen-specific activation occurs only 7 days after Canonically, the production of IFN-γ by Th1 cells, CD8
infection despite the presence of antigen-specific T cells T cells, and other lymphocytes is considered essential
(279), suggesting that antigen-specific responses are for protection against mycobacterial infections. In hu-
delayed by mechanisms other than trafficking of CD4 man immunogenetics studies, Mendelian susceptibility
T cells from the mediastinal lymph nodes to the lungs. to mycobacterial disease (MSMD) is a spectrum of
Delay in the initiation of adaptive immune responses to genetic mutations in five autosomal genes (IFNGR1,
M. tuberculosis infection may be due to a variety of fac- IFNGR2, STAT1, IL12B, IL12RB) and an X-linked
tors, including slow growth of the bacterium, inhibited gene that confer susceptibility to avirulent environmen-
apoptosis of infected macrophages and neutrophils, and tal mycobacteria and BCG (284). Deficiencies related
delayed activation and migration of DCs, which cumu- to IFN-γ signaling in young patients with mutations
latively allow M. tuberculosis to establish a persistent in IFNGR1 and IFNGR2 confer fatal susceptibility to
infection in the lung. mycobacterial infections (285–288). STAT1 is an in-
CD4 T cells interact with infected macrophages to tracellular molecule important for IFN-γ signaling, and
restrict intracellular M. tuberculosis replication. Thus, individuals with heterozygous germline STAT1 muta-
the effectiveness of the CD4 T-cell response depends on tions lose gamma-interferon activating factor (GAF) ex-
proper homing of antigen-specific CD4 T cells from pression (289). GAF is an important transcription factor
lymphoid tissues to M. tuberculosis-infected cells in the that facilitates IFN-γ-induced gene expression. Individ-
lung. In M. tuberculosis-infected mice, antigen-specific uals with heterozygous STAT1 mutations have impaired
CD4 T cells expressing CXCR3 localized to the lung nuclear accumulation of GAF and suffer from recur-
parenchyma and were more efficient at controlling bac- rent mycobacterial infections (289). Additionally, mu-
teria following M. tuberculosis infection when compared tations affecting IL-12 expression levels and signaling
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also confer susceptibility to mycobacterial infections. (314), it is possible that adaptive immunity at stages of
Two mutations in the leucine zipper domain of NEMO, infection when bacterial burden is high may be com-
an intracellular protein involved in NF-κB activation, promised by T cell-derived IL-10. T-bet is a member
impairs CD40-mediated IL-12 production in mono- of the T-box family of transcription factors that is en-
cytes and DCs (290) and leads to recurrent mycobacte- coded by Tbx21 and is the master transcriptional regu-
rial infections. Similarly, defects that impair IL-12p40 lator for lineage commitment to the Th1 subset (315).
lead to decreased IFN-γ levels and confer susceptibility Interestingly, adoptive transfer of T-bet knockout ESAT-
to mycobacterial infections (291–294). Mutations in 6-specific T-cell receptor-transgenic CD4 T cells skewed
IL12RB are the most frequent genetic factors associated toward Th1 in vitro retains the capacity for early pro-
with Mendelian susceptibility to mycobacterial disease, tection against M. tuberculosis infection (316), suggesting
but recurrent mycobacterial susceptibility in individ- that protection conferred by Th1 cells may be indepen-
uals with IL12RB mutations can be mitigated with dent of T-bet or IFN-γ production. Taken together, these
BCG vaccination or primary BCG disease (291, 292, studies demonstrate a clear requirement for the IL-12/
295–298), suggesting that IL-12/IL-23 signaling may not IFN-γ axis in immunity against M. tuberculosis infection
be completely required for secondary immunity. IFN-γ in humans and animal models. Further studies delineat-
is readily detected in human BAL in patients with TB ing the mechanisms underlying IFN-γ- and Th1-mediated
disease and decreases following therapy (299), which is immunity against M. tuberculosis are warranted.
likely a consequence of decreasing bacterial loads. In Although Th1 responses are important for immunity
contrast, studies of human peripheral blood mononu- against TB, studies have also demonstrated that CD4
clear cells show a decrease in IFN-γ responses in ATB T-cell subsets secreting IL-17 (Th17) and FoxP3+ regu-
patients compared to controls (300–305). Lower fre- latory CD4 T cells contribute to the response against
quencies of M. tuberculosis-specific IFN-γ responses in M. tuberculosis infection. There are context-dependent
ATB patients may reflect trafficking of these cells to the beneficial or detrimental roles for Th17s during infec-
lungs, resulting in specific depletion from the periphery. tion with M. tuberculosis. Infection with a W-Beijing
IFN-γ secretion is also an important tool leveraged for lineage strain of M. tuberculosis, HN878, induce Th17
the detection of M. tuberculosis-specific CD4 T-cell responses, and mice deficient in IL-17 display increased
responses in humans and in animal models. Genome- bacterial burden following infection (317). IL-17 re-
wide analysis of M. tuberculosis-specific CD4 T-cell ceptor A subunit knockout mice (318) and IL-17A
epitopes in LTBI individuals revealed three broadly knockout mice (319) also displayed impaired long-term
immunodominant antigenic islands related to bacterial control of high-dose infection with H37Rv. Transfer of
secretion systems recognized by IFN-γ secreting CD4 BCG-specific, IFN-γ knockout Th17 cells into M. tuber-
T cells (306). Animal models of TB also demonstrate a culosis infected, T cell-deficient mice conferred enhanced
key role for IFN-γ in immunity against M. tuberculosis protection and prolonged survival compared to transfer
infection. Mice deficient in IFN-γ succumb to low-dose of naive IFN-γ knockout CD4 T cells (320), suggesting
M. tuberculosis infection (307, 308). Correspondingly, that Th17 cells can mediate protection independently
mice lacking IL-12 are also unable to control M. tuber- of IFN-γ. In humans, significant frequencies of IL-17-
culosis infection (253, 309, 310). The antimycobacterial producing CD4 T cells were found in the peripheral
effects of IFN-γ in mouse models are broadly related to blood mononuclear cells and BAL of BCG-vaccinated
the induction of AMPs, iNOS, and cytokines that acti- healthy individuals and declined in patients with active
vate infected macrophages to restrict intracellular bac- disease (321). Further, individuals with bi-allelic RORC
terial replication, though other mechanisms underlying loss-of-function mutations displayed impaired IL-17
IFN-γ-mediated immunity to M. tuberculosis infection and IFN-γ responses and were susceptible to mycobac-
are still being elucidated. IL-10-deficient mice are less terial disease and candidiasis (322). The generation of
susceptible to M. tuberculosis infection due to an en- Th17 responses to M. tuberculosis in vitro requires
hanced Th1 response (311), suggesting that IL-10 limits costimulation through the CD40-CD40L pathway since
Th1 immunity during M. tuberculosis infection. How- the absence of CD40 on DCs or CD40L on CD4 T cells
ever, Th1 cells secreting IL-10 can also impair host con- attenuates antigen-specific IL-17 responses (268). Acti-
trol of M. tuberculosis infection (312), and CD4 T cells vation of M. tuberculosis-infected DCs through CD40
producing both IFN-γ and IL-10 are detected in the BAL promoted enhanced antigen-specific Th1 and Th17
of ATB patients (313). Given that IL-10 secretion by Th1 responses that contributed to better control of bacterial
cells has been shown to be a result of high antigen dose burden in vivo (268), suggesting that a balanced Th1
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Sia and Rengarajan
and Th17 response is desirable for immunity against (339), highlighting a role for TLR-2-mediated recruit-
M. tuberculosis. The precise role of Th17 cells in pro- ment of T-regs in limiting tissue pathology at chronic
tective immunity to M. tuberculosis remains unclear but stages of disease. Taken together, these results suggest
may be related to their role in the development of less that the functional contribution of T-regs to immunity
hypoxic granulomas (323), in the recruitment of Th1 against M. tuberculosis infection and outcome of disease
cells (324), or in the induction of CXC-chemokines and may be dependent on multiple factors, including strain of
B-cell follicles (325). However, unrestrained IL-17 res- bacteria and stage of infection.
ponses have also been shown to promote detrimental In humans and animal models, M. tuberculosis
immunopathology, typically through pathological neu- establishes a persistent infection despite the induction
trophilia. IFN-γR1 knockout animals (326) or IFN-γR1 of adaptive immune responses. Persistent inflammation
bone marrow chimeric mice selectively lacking the re- and chronic antigen exposure precedes functional ex-
ceptor in nonhematopoietic cells (327) display amplified haustion due to chronic antigenic stimulation. In con-
Th17 responses following M. tuberculosis infection that trast to the expression of Ag85B, which decreases early
lead to a pathogenic accumulation of neutrophils detri- following infection, ESAT-6 is expressed by M. tuber-
mental to the host, suggesting that IFN-γ signaling serves culosis throughout infection (340, 341). Multiple studies
a regulatory role by limiting excessive IL-17-mediated examining CD4 T-cell responses to ESAT-6 and Ag85B
neutrophilia. have suggested that antigen-specific responses are dic-
FoxP3+ CD4 T cells, or T-regulatory cells (T-regs), tated by bacterial expression of those antigens through-
can impair antimycobacterial T-cell responses and con- out infection. CD4 T cells specific for ESAT-6 display a
tribute to disease but can also limit overt inflammation. terminally differentiated phenotype with evidence for
FoxP3+ T-regs can be found in the peripheral blood and functional exhaustion, which runs in contrast to Ag85B-
airways of M. tuberculosis-infected macaques (328) and specific CD4 T cells that appear functional but are quickly
humans (329–334). In mice, T-regs accumulate in the diminished (272, 342–347). Indeed, a vaccine that con-
lung-draining lymph nodes and the lungs following low- tains ESAT-6, Ag85B, and Rv2660c, which is expressed
dose aerosol M. tuberculosis infection (335). Importantly, at late stages of infection, demonstrated enhanced efficacy
FoxP3+ T-regs localized to pulmonary areas adjacent to compared to BCG or to a vaccine containing ESAT-6 and
effector CD4 T cells and depletion of T-regs before and Ag85B (348), suggesting that rational incorporation of
early after infection-enhanced control of bacterial burden antigens present at different stages of infection may im-
(335). Further, M. tuberculosis-specific T-regs delay the prove vaccine efficacy. A clearer understanding of pro-
expansion of antimycobacterial CD4 and CD8 T cells tective CD4 T-cell immunity will require further studies
and, consequently, transfer of M. tuberculosis-specific of the spectrum of antigens recognized by CD4 T cells
T-regs confers increased susceptibility to infection (336). following infection with M. tuberculosis in animal models
Regulation of T-regs during M. tuberculosis infection and in humans.
may be mediated by Th1 responses since M. tuberculosis-
specific T-regs are selectively eliminated following IL-12 Role of CD8 T Cells in M. tuberculosis Infection
driven T-bet expression (337). The functional properties Mice with gene deletion of β2 microglobulin, which
of T-regs responsible for limiting antimycobacterial CD4 abrogates MHC class I antigen presentation, or mice
and CD8 responses remains unclear. IL-10 was not found depleted of CD8 T cells live longer than corresponding
to be secreted by T-regs in mice infected with H37Rv disruptions to the MHC class II pathway or CD4 T-cell
(335). In contrast, T-regs from mice infected with the responses following M. tuberculosis infection (270).
W-Beijing strain, HN878, were found to secrete IL-10, Regardless, CD8 T cells contribute significantly to im-
express inhibitory receptors, and expand to greater de- munity against M. tuberculosis infection. Mice lacking
grees compared to infection with H37Rv (209), sug- TAP-1 (transporter associated with antigen processing
gesting that IL-10 secretion by T-regs may be dependent 1) antigen presentation molecules have deficient CD8
on bacterial strain. Notably, the expansion of T-regs in T-cell responses and succumb more rapidly following
the lungs of mice and outbred guinea pigs infected with M. tuberculosis infection compared to wild-type con-
W-Beijing strains occurred concurrently with a loss of trols (349, 350). Depletion of CD8 T cells in rhesus
Th1 responses and is associated with severe pulmo- macaques compromises protective immunity from BCG
nary pathology (209, 338). However, progressive loss vaccination or chemotherapeutic interventions (57), sug-
of T-regs in chronically infected TLR-2 knockout mice gesting that CD8 T cells are important components of
was associated with increased pulmonary inflammation recall responses to M. tuberculosis infection. Similarly,
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in a mouse model of latency induced by antibiotic treat- itory molecules, including PD-1 and CTLA-4, among
ment, CD8 T-cell responses were found to be important M. tuberculosis-specific CD4 T cells has been shown to
in preventing reactivation (351). The importance of decrease following treatment (366, 367). Importantly,
CD8 T cells during M. tuberculosis infection is related expression of PD-1 on antigen-specific CD4 T cells from
to their secretion of cytokines and cytolytic effector LTBI was not associated with decreased effector func-
molecules that can limit bacterial replication. In addi- tions, and these cells proved to be polyfunctional with
tion to IFN-γ and TNF-α, CD8 T cells secrete perforin to respect to cytokine production upon antigen restimula-
lyse M. tuberculosis-infected macrophages (352). CD8 tion (368), suggesting that PD-1 may be an indicator of
T cells can also release granulysin in cytotoxic granules bacterial burden and CD4 T-cell activation rather than
to directly kill intracellular M. tuberculosis (353, 354). functional exhaustion. However, there is some in vitro
The use of anti-TNF-α therapy in patients with rheu- evidence from human samples suggesting that blockade
matoid arthritis depletes a subset of effector memory of PD-1/PD-L1 interaction can prevent M. tuberculosis-
CD8 T cells that secrete granulysin and express cell specific CD4 T-cell apoptosis (369) and enhance CD8
surface TNF (355), which may partially explain the in- T-cell degranulation and antigen-specific IFN-γ responses
creased progression from LTBI to ATB in patients under- from the peripheral blood mononuclear cells of a subset
going anti-TNF-α therapy. Human CD8 T cells respond of high-responding ATB patients (370). There is evidence
to epitopes in CFP10 (356), ESAT-6 (357, 358), and the that T-cell responses during ATB disease are less poly-
Ag85 complex (359, 360). A variety of human CD8 T-cell functional and have limited proliferative capacity com-
clones tested against a panel of synthetic peptides derived pared to LTBI individuals (371, 372), but whether this
from immunodominant M. tuberculosis antigens revealed functional impairment is mediated by inhibitory recep-
that CD8 T-cell responses are concentrated toward a tors such as PD-1 remains unclear. PD-1-deficient mice
limited set of epitopes and are generally restricted by the infected with M. tuberculosis have increased bacterial
HLA-B allele (361, 362). M. tuberculosis escape from the burden, neutrophilic infiltration, overt inflammation,
phagosome and induction of apoptosis by M. tuberculosis- tissue necrosis, and diminished lifespan compared to
infected macrophages can promote cross-presentation of wild-type mice (373), suggesting that PD-1 is required to
M. tuberculosis antigens to CD8 T cells. However, as pre- prevent aberrant inflammation during M. tuberculosis in-
viously discussed, virulent M. tuberculosis has been shown fection. Further, adoptive transfer studies demonstrated
to inhibit host apoptosis and favor necrosis to circumvent that PD-1-expressing CD4 T cells are highly proliferative
efficient induction of CD8 T-cell responses. All considered, (342, 346), and CD4 T cells lacking PD-1 can drive pa-
CD8 T cells are a critical component of adaptive immunity thology and mortality following M. tuberculosis infec-
to M. tuberculosis infection and play an important role in tion (374), together suggesting that PD-1 may mark
different disease contexts by limiting reactivation during functional CD4 T cells with intrinsic capacity for im-
latency and by directly participating in antimicrobial munoregulation. T-cell immunoglobulin and mucin do-
functions during active infections. main-containing 3 (Tim-3) is another inhibitory receptor
shown to play a role in mediating antimicrobial re-
Inhibitory Receptors During sponses by binding to one of its ligands, galectin-9 (375),
M. tuberculosis Infection and inducing the production of IL-1β by human and
Chronic viral infections, such as HIV, induce the ex- murine macrophages infected with M. tuberculosis (375,
pression of coinhibitory receptors on the surface of 376). In contrast to PD-1, Tim-3-deficient mice were
T cells that can dampen T-cell functionality. Abrogation less susceptible to M. tuberculosis infection, and Tim-3
of coinhibitory receptor ligation has been shown to blockade was shown to improve antigen-specific CD4
be a viable strategy to revitalize functionally exhausted and CD8 T-cell cytokine expression (377), suggesting
virus-specific T-cell responses. The evidence for the im- that Tim-3 may play a role in limiting T-cell responses
portance of coinhibitory receptors during M. tubercu- by promoting functional exhaustion. However, Tim-3-
losis infection in animal models and in human samples expressing, M. tuberculosis-specific T cells from ATB
varies between human and small animal models and patients were functionally superior to T cells expressing
between the specific inhibitory receptor studied. PD-1, low levels of Tim-3. Further, small interfering RNA- or
CD160, and 2B4 are inhibitory receptors associated antibody-mediated disruption of Tim-3 signaling on the
with CD8 T-cell dysfunction in chronic viral infections T cells from ATB patients led to attenuated IFN-γ and
(363, 364) but are expressed at low levels on M. tuber- TNF-α production by Tim-3-expressing T cells, while
culosis-specific CD8 T cells (365). Expression of inhib- Tim-3 ligation augmented IFN-γ production (378). The
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Sia and Rengarajan
mechanisms underlying the roles of receptors such as revealed significant changes in B-cell-associated genes in
PD-1 and Tim-3 require further study and may deviate TB patients after initiation of TB treatment (394). No-
from their role in viral immunity. The evidence accu- tably, antibodies to M. tuberculosis proteins have been
mulated thus far suggests that these molecules mark reported in the sera of TB patients (395), and antibodies
functional T cells that play important roles in antimi- identified in a subset of health care workers exposed
crobial activity and prevention of uncontrolled inflam- to M. tuberculosis provide modest protection in vitro
mation following M. tuberculosis infection. and in a mouse model of infection (396). Utilization
of a high-throughput approach to identifying antibody
Memory T-Cell Responses targets in the M. tuberculosis proteome revealed a set
In humans, antigen-specific memory T-cell responses of extracellular antigens recognized by antibodies in
have been detected in individuals with LTBI and in TB the plasma of patients with ATB (397), suggesting that
patients following successful treatment and cure. Mem- B cells are active participants in immunity to M. tuber-
ory T-cell subsets can be identified according to their culosis infection. B-cell-deficient mice have elevated
cell surface phenotype and functional properties, and neutrophilic recruitment and exacerbated lung immu-
distinct populations of antigen-specific memory T cells nopathology following M. tuberculosis infection (398),
can be categorized based on their expression of a panel which is mediated through enhanced IL-17 responses
of cell surface activation markers and chemokine recep- in M. tuberculosis-infected B-cell-deficient or B-cell-
tors (379). Characterization of M. tuberculosis-specific depleted animals (399). These studies suggest that B cells
memory CD4 T cells in LTBI indicated that these cells can influence the outcome of M. tuberculosis infection
did not express activation markers and were largely of by moderating inflammatory responses. Antibody pro-
a CD45RA-CCR7 phenotype descriptive of T effector duction by B cells can promote divergent outcomes
memory cells (368, 380). In contrast, analysis of LTBI (400). Binding of antibody to the inhibitory Fc gamma
individuals using MHC class II tetramers revealed a pop- receptor II B attenuates macrophage IL-12 produc-
ulation of tetramer+CD45RA-CCR7+ central memory tion and negatively impacts Th1 responses (401), while
CD4 T cells that further expressed CXCR3+CCR6+ passive transfer of monoclonal antibodies specific for
(306), highlighting the heterogeneity of memory CD4 M. tuberculosis cell wall components can improve the
T-cell phenotypes that can vary based on antigen spec- outcome of infection in mice (390). B-cell secretion of
ificity, disease status, and manner in which specific re- cytokines can also influence M. tuberculosis-infected
sponses are identified. Human memory CD8 T cells are macrophages. Type I IFN expression by murine B cells
predominantly terminally differentiated effector memory and B cells from pleural effusion of TB patients altered
T cells in individuals with LTBI (365, 381). Memory macrophage polarization toward an anti-inflammatory
T-cell responses have also been studied in the context phenotype (402). Taken together, these studies highlight
of “memory-immune” mice, which are M. tuberculosis- a role for B cells, which constitute a significant popula-
infected mice that subsequently receive antibiotic treat- tion of lymphocytes around lung granulomas in the
ment. In this context, both memory CD4 (382, 383) and adaptive immune response to M. tuberculosis infection
CD8 (384, 385) T cells play a role in immunity against by modulating inflammation through the secretion of
M. tuberculosis infection. T cells from memory-immune antibodies and cytokines.
mice expanded rapidly, secreted IFN-γ, and conferred a
significant level of protection at early timepoints after γδ, CD1-Restricted T Cells, and MAIT Cells
infection (383, 386–388) but are ultimately unable to in Immunity against M. tuberculosis
confer long-term protection (389), suggesting that mem- γδ T cells are a population of T cells that express a re-
ory T cells generated after primary M. tuberculosis in- stricted repertoire of T-cell receptor genes, recognize
fection have limited capacity to protect from reinfection. nonpeptide antigens such as microbial metabolites and
phosphoantigens (403), and can be found at mucosal
B-Cell and Antibody Responses surfaces including the lung (404). γδ T cells proliferate
During M. tuberculosis Infection when exposed to M. tuberculosis-infected monocytes
There is a body of evidence suggesting that humoral (405). Multiple M. tuberculosis metabolites, includ-
immunity plays a role in defense against M. tuberculosis ing pyrophosphate, prenyl pyrophosphate derivatives
infection (reviewed in 390). B cells can be found along- (406, 407), and triphosphorylated thymidine-containing
side T cells in the lymphocytic cuff in human granulomas compounds (408), are recognized by human γδ T cells.
(391–393), and whole blood gene expression analysis Human γδ T cells can also respond to mycobacterial
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heat shock proteins (409), though this response may family of M. tuberculosis lipopeptides called didehydroxy-
be dependent on BCG immunization (410). Vγ9Vδ2- mycobactins are presented by CD1a (435), and a variety
expressing γδ T cells represent a significant proportion of phospholipid antigens are presented by CD1c (425).
of M. tuberculosis-reactive T cells in peripheral blood The precise role of CD1-restricted T cells in immunity
(411–413) and can restrict intracellular M. tuberculosis during M. tuberculosis infection remains unclear, and
replication in macrophages (414). Interestingly, Vγ9Vδ2 further studies of their function in the periphery and es-
T cells can function as antigen presentation cells via pecially in BAL would inform their potential as targets for
provision of CD40 costimulation to promote the ex- TB vaccines.
pansion of αβ T cells with enhanced capacity to restrict MAIT cells are a subset of T cells with innate-like
intracellular BCG replication (415). Additionally, human qualities enriched in mucosal tissues, including the in-
Vγ2Vδ2 T cells recognize M. tuberculosis (416), and in testinal mucosa, lung, and liver (436–438). These cells
NHPs, Vγ2Vδ2 T cells are expanded by phosphoantigen recognize antigen through a nonpolymorphic MHC class
and IL-2 administration (417). Adoptively transferred I-related molecule 1 (439) presenting pterin-containing
Vγ2Vδ2 T cells into naive animals confer protection byproducts of riboflavin synthesis in bacteria and fungi
against M. tuberculosis infection (418). γδ T cells have (440). In humans, MAIT cells express a semi-invariant
been shown to mediate direct killing of M. tuberculosis Vα7.2 and CD161 and can either be double negative
via secretion of granulysin and perforin (419) or through for CD4 and CD8 or CD4-CD8+ (436, 441). MAIT cells
the induction of TNF-α by monocytes (420). There is also have been described in the peripheral blood of healthy
evidence that γδ T cells can influence DC cross talk with individuals and are depleted in ATB patients (442),
T cells by promoting DC maturation and expression of possibly reflecting migration into the lung. These cells
costimulatory molecules (421). In mice, γδ T cells accu- produce IFN-γ and TNF-α upon activation (442, 443),
mulate in the lung-draining lymph nodes, are responsive but their contribution to the immune response to M. tu-
to M. tuberculosis antigen independent of MHC class II berculosis infection requires further study.
(422), and are significant sources of early IL-17 produc-
tion following M. tuberculosis infection (423).
Due to the large repertoire of glycolipids present on INITIATION AND HETEROGENEITY
the mycobacterial cell wall, a significant T-cell response OF THE GRANULOMA
is directed at glycolipid antigens presented by the CD1 The granuloma is a hallmark histopathological structure
family of molecules. CD1 molecules are a family of in TB. It represents host sequestration of bacteria to limit
MHC class I-like antigen presentation molecules that dissemination as well as a niche for long-term persis-
present glycolipid antigens to T cells. There are five CD1 tence of M. tuberculosis. Further, the selectively drug-
family members in humans, split into two groups based permeable nature of the TB granuloma can diminish
on sequence homology. Group 1 molecules include CD1a, the efficacy of drugs meant to treat persistent bacteria
CD1b, CD1c, and CD1e. CD1d is the sole inclusion in (444). The granuloma is composed of an aggregate of
group 2 (424). Mycobacterial lipids are readily presented M. tuberculosis-infected and -uninfected macrophages
by CD1 molecules in human cells, but mechanistic studies in varying stages of maturation and differentiation
of this family of molecules is limited because mice only (445–447). Macrophages in the granuloma can undergo
express two orthologs of CD1d and do not express group an epithelioid transformation, become lipid-filled foamy
1 molecules. Nevertheless, studies in human cells revealed macrophages, or merge into multinucleated giant cells.
that mycobacterial lipids presented by group 1 CD1 mole- This central core of macrophages is accompanied by
cules promote T-cell proliferation and cytokine produc- neutrophils, DCs, and fibroblasts circumscribed by T
tion (425–432). Mycobacterial glycerol monomycolate, and B lymphocytes and progressively becomes a hypoxic
glucose monomycolate, sulphoglycolipids, and mycolic environment where many cells undergo necrotic death to
acid can be presented through CD1b (426–428, 433). form an acellular core termed the caseum (448). The
CD1b-restricted T cells expand and secrete IFN-γ and IL-2 granuloma is a hallmark structure in human TB that is
upon interaction with cognate antigen and contract fol- modeled variably among available animal models.
lowing anti-TB therapy (430). Interestingly, use of CD1b C57BL/6 and BALB/C mice do not naturally recapitulate
tetramers loaded with glucose monomycolate revealed the human granuloma in that lung lesions are rarely
that CD1b-restricted T cells are antigen-specific and also necrotic and caseating. The animal models that most
express CD4 (429, 434). M. tuberculosis lipids presented closely recapitulate the heterogeneity of human granu-
through CD1a and CD1c have also been identified. A lomas include certain susceptible inbred mouse strains
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Sia and Rengarajan
that present with necrotizing granulomas (C3HeB/FeJ, (454). T-cell functionality in the granuloma may there-
DBA/2, CBA/J, I/St), guinea pigs, rabbits, and the NHP fore be a function of disease status and proximity to the
model. Additionally, the zebrafish model has also bacteria-containing, hypoxic, and necrotic core of the
yielded fundamental insights into the initiation and dy- TB granuloma. Additionally, T cells near the granuloma
namics of the tuberculous granuloma. can be negatively impacted by the depletion of key
The transparency of zebrafish larvae has made direct amino acids required for proper function. As mentioned
visualization of the initiation of the granuloma possible previously, IDO, an enzyme that functions in the ca-
following infection with M. marinum (48). Studies based tabolism of tryptophan, is expressed by cells in the core
on this model have revealed that the innate immune re- of the granulomas of rhesus macaques infected with
sponse is sufficient to initiate the granuloma following M. tuberculosis (283), and inhibition of IDO promoted
infection. Recruitment of additional macrophages me- granuloma reorganization and attenuated disease (66).
diated, in part, by mycobacterial ESX-1 proteins initiates The functionality of T cells within granulomas may also
a cascade of events that leads to the establishment of be regulated by direct cross talk with infected myeloid
the mycobacterial granuloma (221, 449). Importantly, cells, including macrophages and DCs. Intravital imag-
recruited macrophages can traffic through the initial ing of mycobacteria-induced liver granulomas revealed
granuloma to phagocytose apoptotic infected macro- limited antigen-specific T-cell migration arrest in re-
phages and egress to form distal secondary granulomas sponse to infected myeloid cells (345), suggesting that
(450). Mycobacterial lipids play a key role in establish- T cells do not interact meaningfully with infected cells in
ing the granuloma by limiting macrophage effector granulomas. Taken together, these studies highlight the
functions and promoting the recruitment of additional vast complexity and heterogeneity of the TB granuloma.
macrophages to facilitate dissemination. In particular,
mycobacterial phthiocerol dimycocerosate can mask
TLR-signaling and prevent induction of nitrosative IMMUNOLOGY OF TB DIAGNOSTICS
stresses (451), and mycobacterial PGL can induce mac- TB diagnosis relies on evaluation of clinical symptoms
rophage production of CCL2 to recruit CCR2+ mono- and patient history combined with radiographic exam-
cytes that permit bacterial dissemination (452). These ination and detection of bacteria in sputum (9). The
studies collectively indicate that the initiation of the presence of acid-fast bacilli in sputum smears by mi-
mycobacterial granuloma is dependent on recruitment croscopy does not specifically indicate infection with
of bacteria-permissive macrophages and monocytes fol- M. tuberculosis; microbiological culture and nucleic
lowing initial infection and can be mediated by myco- acid amplification-based tests are required to confirm the
bacterial secreted factors and membrane lipids. presence of M. tuberculosis infection. Xpert MTB/RIF, a
TB granulomas can vary in their cellular composition, cartridge-based near-patient diagnostic assay utilizing
oxygenation levels, inflammatory milieu, and bacterial real-time nucleic acid amplification of M. tuberculosis
burden. This heterogeneity can exist between and within DNA, which also detects drug resistance to the first-line
infected hosts. Infection of cynomolgus macaques with drug rifampicin, is recommended by the World Health
a panel of M. tuberculosis isolates that differed by a Organization for TB diagnosis (455, 456). IFN-γ release
single nucleotide polymorphism revealed that individual assays (IGRAs), which leverage the specificity of the
granulomas can be founded by a single bacterium and immune response to M. tuberculosis, are the basis of
can vary in their bacterial burden compared to other the QuantiFERON-TB Gold In-Tube and T-SPOT.TB
granulomas within the same host (51). Analysis of T-cell diagnostic assays. IGRAs measure IFN-γ produced by
functionality between sterile and nonsterile granulomas antigen-specific T cells in blood that recognize M. tuber-
revealed a modest association between IL-10 and IL-17 culosis antigens (ESAT-6, CFP-10, TB7.7) (457). IGRAs
responses and clearance of M. tuberculosis in sterile provide increased specificity over traditional Mantoux
granulomas (453). However, in the context of TNF-α skin tests that depend on delayed-type hypersensitivity
neutralization in latently infected macaques, IL-10 and reactions to purified protein derivative, which is not
IL-17 responses were associated with animals at higher specific to M. tuberculosis infection, and positive results
risk of reactivation (71). Proteome analysis of laser- may be due to BCG vaccination or exposure to envi-
capture microdissected human and rabbit lung lesions ronmental mycobacteria. However, IGRAs do not dif-
suggests that inflammatory responses typical of the ferentiate between active and latent TB and cannot be
center of the TB granuloma are physically segregated used to diagnose TB disease. While sputum-based smear
from anti-inflammatory responses in adjacent lung tissue and culture techniques are established worldwide for
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clinical indication of M. tuberculosis infection, collec- aim for in a TB vaccine. MVA85A is a modified vaccinia
tion of sputum, especially from children, can be chal- Ankara virus expressing Ag85A from M. tuberculosis
lenging and is not completely reliable. Therefore, there that was utilized as a booster vaccine in infants previ-
is interest in developing non-sputum-based diagnostic ously vaccinated with BCG (472). Notably, vaccination
approaches for TB. Detection of urinary lipoarabino- with MVA85A enhanced frequencies of antigen-specific,
mannan in suspected TB cases is being investigated in polyfunctional CD4 T cells co-expressing IFN-γ, IL-2,
HIV-infected (458) and -uninfected (459) individuals. and TNF-α (472). Although MVA85A vaccination en-
Blood-based biomarkers discriminating between LTBI and hanced antigen-specific CD4 T-cell responses, it did not
ATB are being investigated for potential application to TB provide added protection against TB disease in infants
diagnostics and treatment response (460–462). HLA-DR, (472). Other viral-vectored vaccines in various stages of
CD38, and Ki67 expression on M. tuberculosis-specific development include Ad5Ag85A (473), ChAdOx1.85A
CD4 T cells from peripheral blood is reported to be a + MVA85A (474), MVA85A-IMX313 (475), and TB/
highly specific and sensitive method to discriminate LTBI FLU-04L. Additionally, a recent study utilizing a recom-
and ATB and evaluate treatment response (460). A recent binant cytomegalovirus demonstrated protection in rhesus
study suggests that HLA-DR could function as a robust macaques (476). While viral vectors do not require the use
marker distinguishing LTBI and ATB in HIV-infected of adjuvants, previous exposure to the vector may attenu-
populations (461). Further understanding of the spectrum ate vaccine-induced responses and represents a potential
of antigen-specific responses to M. tuberculosis infection complication to the use of viral vectors. Whole-cell vaccines
can be leveraged to develop diagnostics that can monitor currently under development include killed Mycobacte-
infection and treatment response. rium vaccae, DAR-901 (477), VPM1002, MTBVAC, and
RUTI. VPM1002 is an approach to improve BCG immu-
nogenicity and vaccine potential by engineering BCG to
TB VACCINES express lysteriolysin from Listeria monocytogenes to es-
The only currently licensed vaccine against TB is ba- cape the phagosome and carry a urease deletion mutation
cillus Calmette-Guérin (BCG), an attenuated strain of that facilitates phagosomal acidification, thereby enhancing
M. bovis (463, 464). BCG confers protection against MHC class I antigen presentation to CD8 T cells (478).
severe forms of TB, including miliary TB and TB men- MTBVAC is a genetically attenuated M. tuberculosis strain
ingitis (465), but does not reliably protect against pul- lacking phoP and fadD26 that abrogates synthesis of var-
monary TB in children or adults (3, 4, 466). The lack ious surface lipids (479). Lastly, the therapeutic vaccine
of validated correlates of protection against TB is a se- candidate RUTI was developed by growing M. tuberculosis
vere limitation to TB vaccine development. Despite the under stress prior to fragmentation, detoxification, and
importance of IFN-γ responses in resistance against delivery in liposomes to individuals with LTBI to prevent
M. tuberculosis infection in humans and animal models, progression to ATB (480–482).
accumulating evidence suggests that induction of en- There have been substantial advances in our under-
hanced IFN-γ responses is not sufficient to obtain a more standing of immunity against M. tuberculosis from the
efficacious TB vaccine. Indeed, the frequency and func- days of Drs. Calmette and Guérin. Nevertheless, the ab-
tional profile of BCG-specific CD4, CD8, and γδ T cells sence of suitable alternatives to BCG highlights the
from whole blood, including IFN-γ-producing T cells, challenges before us. M. tuberculosis is adept at sub-
did not correlate with protection against TB in newborns verting the cross talk between innate and adaptive im-
(467). As of 2017, there are 14 TB vaccine candidates in munity, and it will be important to understand that cross
varying phases of clinical development representing talk for the rational development of better vaccines. Even
three broad strategies: subunit vaccines pairing M. tu- in the absence of protective correlates and in the face of
berculosis antigens with adjuvants, viral-vectored vac- disappointing preliminary results for MVA85A, the state
cines utilizing an attenuated virus for antigen delivery, of TB vaccine development is resurgent now more than
and whole-cell vaccines utilizing attenuated M. tuber- ever and provides cause for optimism for the development
culosis or related mycobacterial species. Protein subunit of more efficacious vaccines and therapeutics against TB.
vaccines currently under clinical development include
M72/AS01E (468), H4:IC31 (469), H56:IC31 (470), REFERENCES
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