T Cell-mediated Immunity

&
Effector Mechanism of
T Cell-mediated Immunity

Tim MKK Imunologi

FK Universitas Brawijaya
2020
Immune Response
Tujuan Pembelajaran/Learning
Objectives
Mahasiswa mampu memahami dan menjelaskan mengenai:

1. Tahapan respons sel T

2. Pengenalan antigen dan kostimulasi
3. Respons fungsional limfosit T terhadap antigen dan
kostimulasi
4. Migrasi limfosit T pada reaksi imun seluler
5. Tipe reaksi imun seluler
6. Perkembangan dan fungsi Limfosit T CD4+ efektor
7. Perkembangan dan fungsi Limfosit T CD8+ efektor
8. Resistensi mikroba patogen terhadap imunitas seluler
T Cell-mediated Immunity
Cell-mediated Immunity (CMI)
Cell-mediated immunity involves spesialized cell called T cell
lymphocyte that recognize intracellular microbes, such as as
virus and bacteria that survive and proliferate inside phagocytes.

Abbas, Abul K., et al. 2016. Basic immunology, 5th edition

Phases of T Cell Responses
1. Antigen Recognition and Costimulation
Naive T cells recognize antigens in the
secondary lymphoid organs through
antigen receptors and co-receptors
2. T Cell Activation
T cell activation leading to proliferation of
the T cells and their differentiation into
effector and memory cells
3. Migration of Effector T Cells
The effector cells perform their functions
when they are activated by the same
antigens in peripheral tissues or lymphoid
organs

Abbas, Abul K., et al. 2016. Basic immunology, 5th edition

ANTIGEN RECOGNITION AND COSTIMULATIONS
The initiation of T cell responses requires multiple receptors on the
T cell recognizing ligand on APCs, such as:
1. T cell receptors (TCR) recognizes MHC associated peptide
antigen
2. CD4 and CD8 coreceptors on T cells recognizes MHC molecules
on the APC and ther TCR complex to deliver activating signals
3. Adhesion molecules strengthen the binding of T cells to APCs
4. Costimulators (B7) which are expressed on APCs bind to
costimulatory receptors on naive T cells thus promoting
responses to infectious pathogens
5. Cytokines amplify T cell responses and direct it along various
differentiation pathways.

Abbas, Abul K., et al. 2016. Basic immunology, 5th edition

 Surface molecules of CD4+ T Cells involved in T cells
activation and their coresponding ligans on APCs

Abbas, Abul K., et al. 2016. Basic immunology, 5th edition

Recognition of MHC-Associated Peptides

• The T cells receptors

(TCR) and CD4 or CD8
coreceptors together
recognize complexes of
peptide antigen and
MHC molecules on APCs
• This recognition provides
initial signal for T cell
activation

Abbas, Abul K., et al. 2016. Basic immunology, 5th edition

 Role of Adhesion Molecules in T Cell Responses
1. Adhesion molecules on T cells recognize their ligands
on APCs and stabilize the binding of the T cells to the
APCs.
2. The most important adhesion molecules belong to
the family of heterodimeric proteins called integrins.
3. The major T cell integrin involved in binding to APCs is
leukocyte function–associated antigen 1 (LFA-1),
whose ligand on APCs is called intercellular adhesion
molecule 1 (ICAM-1)

Abbas, Abul K., et al. 2016. Basic immunology, 5th edition

 Role of Costimulation in T Cell Activation

Costimulators as second signals for T cell activation. Antigen recognition without

co-stimulation may make T cells unresponsive (tolerant).
 Expansion and decline of T cells responses
• Clonal expansion
provides a large pool of
antigen-specific
lymphocytes from
which effector cells can
be generated to
combat infection.
• There is also declining
of T cells, called
contraction, as
homeostasis
mechanism.

Abbas, Abul K., et al. 2016. Basic immunology, 5th edition

Differentiation of Naive T Cells into Effector Cells
• Proliferating T cells
differentiate into CD4+
and CD8+ T cells.
• CD4+ lineage acquire the
capacity to produce
different sets of
cytokines. The subsets of
T cells that are
distinguished by their
cytokine profiles are
named Th1, Th2, and
Th17.
• CD8+ lineage acquire the
ability to kill infected
cells, called cytotoxic
effector cells (CTLs).
Abbas, Abul K., et al. 2016. Basic immunology, 5th edition
 Development of Memory T Lymphocytes
• T cell–mediated immune responses to an antigen
usually result in the generation of memory T cells
specific for that antigen, which may persist for years,
even a lifetime.
• Characteristic of memory T cells :
- Survive even after the infection is eradicated and
antigen is no longer present.
- Rapidly induce to produce cytokines or kills infected
cells on encountering the antigen that they
recognize.
- Can be found in lymphoid organs, peripheral tissue,
especially mucosa and skin, and circulation.
Abbas, Abul K., et al. 2016. Basic immunology, 5th edition
 MIGRATION OF T CELLS
• Types of T cells migration:
- Naive T cells must migrate between blood and
secondary (peripheral) lymphoid organs
throughout the body, until they encounter
dendritic cells within the lymphoid organ that
display the antigens the T cells recognize
- Effector cells migrate back to the sites of infection,
where they function to kill microbes.
• The migration of naive and effector T cells to sites of
infection is controlled by three families of proteins
(selectins, integrins, chemokines).
Abbas, Abul K., et al. 2016. Basic immunology, 5th edition
Migration of naive and effector T lymphocytes
Lymphocytes trafficking
Lymphocytes homing (video)
Summary (T cell mediated immunity)
• T lymphocytes are the cells of cell-mediated immunity, the arm of the
adaptive immune system that combats intracellular microbes, which may be
microbes that are ingested by phagocytes and live within these cells or
microbes that infect nonphagocytic cells. T lymphocytes also mediate defense
against some extracellular microbes and help B lymphocytes to produce
antibodies.
• The responses of T lymphocytes consist of sequential phases: recognition of
cell-associated microbes by naive T cells, expansion of the antigen-specific
clones by proliferation, and differentiation of some of the progeny into
effector cells and memory cells.
• T cells use their antigen receptors to recognize peptide antigens displayed by
MHC molecules on antigen-presenting cells (APCs), which accounts for the
specificity of the ensuing response, and also recognize polymorphic residues
of the MHC molecules, accounting for the MHC restriction of T cell responses.
• Antigen recognition by the T cell receptor (TCR) triggers signals that are
delivered to the interior of the cells by molecules associated with the TCR
(CD3 and ζ chains) and by the coreceptors CD4 and CD8, which recognize class
II and class I MHC molecules, respectively.
Summary (T cell mediated immunity)
• The binding of T cells to APCs is enhanced by adhesion molecules, notably the
integrins, whose affinity for their ligands is increased by antigen recognition by
the TCR.
• APCs exposed to microbes or to cytokines produced as part of the innate
immune reactions to microbes express costimulators that bind to receptors on
T cells and deliver necessary second signals for T cell activation.
• The biochemical signals triggered in T cells by antigen recognition and
costimulation result in the activation of various transcription factors that
stimulate the expression of genes encoding cytokines, cytokine receptors, and
other molecules involved in T cell responses.
• In response to antigen recognition and costimulation, T cells secrete cytokines
that induce proliferation of the antigen-stimulated T cells and mediate the
effector functions of T cells.
• T cells proliferate following activation by antigen and costimulators, resulting
in expansion of the antigen-specific clones. The survival and proliferation of
activated T cells are driven by the growth factor interleukin-2.
Summary (T cell mediated immunity)
• Some of the T cells differentiate into effector cells that are
responsible for eradicating infections. CD4+ effector cells
produce surface molecules, notably CD40L, and secrete
various cytokines that activate other leukocytes to destroy
microbes. CD8+ effector cells are able to kill infected cells.
• Other activated T cells differentiate into memory cells, which
survive even after the antigen is eliminated and are capable of
rapid responses to subsequent encounter with the antigen.
• Naive T cells migrate to peripheral lymphoid organs, mainly
lymph nodes draining sites of microbe entry, whereas many of
the effector T cells generated in lymphoid organs are able to
migrate to any site of infection.
• The pathways of migration of naive and effector T cells are
controlled by adhesion molecules and chemokines. The
migration of T cells is independent of antigen, but cells that
recognize microbial antigens in tissues are retained at these
sites.
 Effector Mechanism of
T Cell-mediated Immunity
Types of T Cell Mediated Immune Reactions
Two types of CMI :
A. CD4+ helper T cells that secrete cytokines that recruit and
activate other leukocytes to phagocytose and destroy
microbes
B. CD8+ cytotoxic T lymphocytes (CTLs) that kill any infected cell
containing microbial proteins in the cytosol
 DEVELOPMENT AND FUNCTION OF CD4+ T CELLS
CD4+ helper T cells may differentiate into three major subsets of
effector cells (Th1, Th2, Th17) that produce distinct sets of
cytokines that perform different functions in host defense.

CD4+ Tcell/
Thelper naive/
Th0

APC

Abbas, Abul K., et al. 2016. Basic immunology, 5th edition

 Development of Th1, Th2, and Th17 effector cells
• Dendritic cells and other
immune cells that
respond to different
types of microbes
secrete cytokines that
induce the development
of CD4+ T cells
• Th1 effector cells is
driven by IL-12 and IFN-γ
• Th2 effector cells is
driven by IL-4
• Th17 effector cells is
driven by IL-1, IL-6, IL-23
and TGF-β

Abbas, Abul K., et al. 2016. Basic immunology, 5th edition

 Th1 Cells
• Th1 subset is induced by
microbes that are ingested by
and activate phagocytes.
• Th1 cells stimulate phagocyte-
mediated killing of ingested
microbes
• The signature cytokine of Th1
cells is interferon-γ (IFN-γ), the
most potent macrophage-
activating cytokine.

Abbas, Abul K., et al. 2016. Basic immunology, 5th edition

 Macrophage activation by Th1 cells

Abbas, Abul K., et al. 2016. Basic immunology, 5th edition

 Th2 Cell
• Th2 cells are induced in
parasitic worm infections and
promote IgE, mast cell and
eosinophil-mediated
destruction of parasites
• The signature cytokines of Th2
cells are IL-4, IL-5 and IL-13
• IL-4 stimulates the production
of IgE antibodies
• IL-5 induce eosinophils bind to
IgE through Fc receptors
• IL-13 stimulates mucus
secretion and intestinal
peristalsis

Abbas, Abul K., et al. 2016. Basic immunology, 5th edition

 Balance between Th1 and Th2 cell activation

Th1 cells activate phagocytes to kill ingested microbes and Th2 cells inhibit classical
macrophage activation. This balance may influence the outcome of infections.
 Th17 Cell
• Th17 cells induce inflammatory reactions
that destroy extracellular bacteria and
fungi and may contribute to several
inflammatory diseases
• The major cytokines produced by Th17
cells are IL-17 and IL-22
• IL-17 stimulates the production of
chemokines from other cells, and these
chemokines are responsible for
leukocyte recruitment
• IL-22 helps to maintain the integrity of
epithelial barriers and may promote
repair of damaged epithelia

Abbas, Abul K., et al. 2016. Basic immunology, 5th edition

DEVELOPMENT AND FUNCTION OF CD8+ T CELL
• CD8+ T lymphocytes activated by antigen and other signals differentiate into
CTLs that are able to kill infected cells expressing the antigen
• CTLs kill target cells mainly as a result of delivery of granule proteins into the
target cells (granzymes and perforin)
T cell killing
 Coorporation between CD4+ and CD8+ T cells
• CD4+ T cells eliminated
phagocytosed microbes in
vesicles and cytosol by
secreting IFN-γ and
activating microbicidal
mechanisms of
macrophages.
• If the microbes are able to
escape from vesicles into
the cytoplasm, their
elimination requires killing
of the infected cells by
CD8+ CTLs.
Abbas, Abul K., et al. 2016. Basic immunology, 5th edition
Evasion of CMI by microbes
Evasion of CMI by microbes
Viral evasion
Summary: Effector Mechanism of T Cell-mediated Immunity
• CMI is the arm of adaptive immunity that eradicates
infections by cell-associated and utilizes two types of T
cells: CD4+helper T cells recruit s. and activate phagocytes
to kill ingested and some extracellular microbes, and
CD8+ cytotoxic T lymphocytes (CTLs) eliminate the
reservoirs of infection by killing cells harboring microbes
in the cytosol.
• Effector cells of the Th1 subset (CD4+) recognize the
antigens of microbes that have been ingested by
macrophages. These T cells secrete IFN-γ and express
CD40 ligand, which function cooperatively to activate
macrophages.
• Th2 (CD4+) cells stimulate eosinophilic inflammation and
trigger the alternative pathway of macrophage activation,
and induced in parallel trigger IgE production. IgE and
eosinophils are important in host defense against
helminthic parasites.
Summary: Effector Mechanism of T Cell-mediated Immunity
• The balance between activation of Th1 and Th2
cells determines the outcomes of many infections.
• Th17 cells enhance neutrophil and monocyte
recruitment and acute inflammation, which is
essential for defense against certain extracellular
bacteria and fungi.
• CD8+ T cells differentiate into CTLs that kill infected
cells, mainly by inducing apoptosis of the infected
cells. CD4+ and CD8+ T cells often function
cooperatively to eradicate intracellular infections.
• Many pathogenic microbes have evolved
mechanisms to resist cell-mediated immunity.
 REFERENCES
Abbas, Abul K., Andrew H. Lichtman, Shiv Pillai. 2016. Basic
immunology, 5th edition
THANK YOU