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Clin Immunol. 2009 January ; 130(1): 27–33. doi:10.1016/j.clim.2008.08.018.
The effects of IL-6 on CD4 T cell responses
Oliver Dienz* and Mercedes Rincon*

* Department of Medicine/Immunobiology Program, University of Vermont, Burlington VT 05405
Abstract
Cytokines have long been known to profoundly influence the adaptive immune response by
determining CD4 T cell differentiation. Although IL-6 has been initially characterized as a B cell
growth factor and inducer of antibody production research from our lab and others has revealed over
the last years that IL-6 also plays a significant role in CD4 T cell differentiation. This review
highlights the variety of ways in which IL-6 affects CD4 effector functions and how this may
contribute to different types of diseases.
Keywords
IL-6; IL-6R; CD4 T cell differentiation; T helper response; Th1/Th2/Th17; IL-21; autoimmune
disease; allergic airway inflammation
Introduction
In a search for factors that promote plasma cell differentiation and antibody production of B
cells, one cytokine now known as IL-6 was discovered in 1986 [1]. In addition to its effects
on antibody production, IL-6 has a strong stimulatory effect on the growth of mouse
plasmacytoma and human myeloma cells [2]. Together with TNFα and IL-1, IL-6 is also
considered a major proinflammatory cytokine important in the protection from pathogens
during an infection. Proinflammatory cytokines are also known to play an important role in
disease progression and tissue damage of autoimmune diseases such as multiple sclerosis,
rheumatoid arthritis, and systemic lupus erythematosus. In the last years, it has become
increasingly clear that IL-6 is an important modulator of CD4 T cell effector functions thereby
shaping the immune response and contributing to inflammation.
The IL-6 receptor and its signaling pathways

IL-6 is a pleiotropic cytokine expressed by antigen presenting cells (APCs) such as dendritic
cells, macrophages and B cells among other cells of the hematopietic system but is also
produced by a variety of non-hematopoietic cells including keratinocytes, fibroblasts, epithelial
cells, and astrocytes [3]. IL-6 production is induced in response to a number of external stimuli
like IL-1, tumor necrosis factor (TNF)α, LPS, and platelet-derived growth factor (PDGF) [3].
IL-6 binds to a receptor complex consisting of the specific IL-6R and the common signaling
component gp130 which is also shared by other cytokines of the IL-6 family (e. g. oncostatin
Corresponding author: Mercedes Rincón, Ph.D., Department of Medicine/Immunobiology Division, Given Medical Building D305,
University of Vermont, 89 Beaumont Ave., Burlington, VT 05405, Phone: 802-656.0937, e.mail: [email protected].
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Dienz and Rincon Page 2
M, leukemia inhibitory factor (LIF), IL-11) [4]. X-Ray crystallography has shown that two
heterotrimers of IL-6, IL-6R and gp130 associate to form a hexameric complex [5]. Through
formation of this complex members of the cytoplasmic Janus kinase (Jak) family of tyrosine
kinases bind to gp130 inducing their kinase activity resulting in phosphorylation of downstream
targets. Jak1 is thought to be most relevant for IL-6 signaling although Jak2 and Tyk2 also
transduce some of the IL-6 signals [4]. The best described substrate for Jaks in IL-6 signaling
is the Signal Transducer and Activator of Transcription (STAT)3, a transcription factor that in
its inactive state remains in the cytoplasm but after phosphorylation through Jaks forms
homodimers that are actively being transported to the nucleus to induce gene transcription
[6]. To a lesser extent, STAT1 has also been involved in IL-6 signaling [7]. Other than STAT
family members, IL-6 stimulation activates the transcription factor CCAAT/enhancer binding
protein (C/EBP)β through the ras-Erk MAPK cascade and further upregulates the expression
of C/EBPδ [4,8]. C/EBP family member are therefore important mediators of IL-6-induced
changes in gene expression. Lastly, phoshpatidyl-inositol (PI)3-kinase has been described as
a signal transducer of IL-6 triggering the activation of Akt and subsequently promoting survival
in many cell types [9].
While gp130 is ubiquitously expressed, IL-6R is present mostly on leukocytes and hepatocytes
[10]. In accordance with its expression pattern, IL-6 regulates acute phase protein production
in the liver as well as proliferation, survival and function of many leukocyte populations [3].
Surprisingly, it was observed that cells lacking IL-6R expression were responsive to IL-6
stimulation especially during inflammatory conditions. This finding led to the discovery of a
soluble form of the IL-6R that lacks the transmembrane domain but retains its ability to bind
to IL-6 and gp130 to form a functional complex in a process called transsignaling of IL-6
[11]. Soluble IL-6R (sIL-6R) can be generated by two mechanisms: 1) Metalloproteinase
mediated cleavage (“shedding”) of the membrane bound form of the IL-6R [12], and 2)
expression of an alternatively spliced IL-6R variant that lacks the transmembrane domain
[13]. Little is known about the regulation of the full-length IL-6R cleavage versus expression
of the alternatively spliced receptor and which cells are the sources of sIL-6R. Neutrophils and
macrophages in addition to some cell lines have been shown to produce sIL-6R [13,14,15].
We have recently demonstrated that human CD4 T cells also produce sIL-6R upon T cell
receptor activation primarily through cleavage of the cell surface IL-6R by the ADAM family
of metalloproteinases [16]. Thus, CD4 T cells at the site of inflammation can not only provide
cytokines but also exert effector functions through release of sIL-6R. In conjunction with cells
that produce high levels of IL-6 such as macrophages and fibroblasts, the presence of the sIL-6R
renders cells lacking the IL-6R, but expressing gp130, responsive to IL-6.
IL-6 in T cell survival and proliferation

IL-6 was initially cloned as a growth factor for B cells and inducer of plasma cell differentiation
[1]. Over the years it has become increasingly clear that IL-6 has also a profound effect on
CD4 T cells. Resting, naïve CD4 T cells undergo apoptosis in in vitro cell culture soon after
isolation from lymphoid mouse tissues suggesting the presence of survival factors in vivo. IL-6
has such anti-apoptotic properties as it prolongs CD4 T cell survival in vitro most likely by
retaining Bcl-2 expression in the isolated T cells [17].
Soon after its discovery, IL-6 was described as a costimulatory molecule for T cell activation
enhancing proliferation independently of IL-2 gene expression [18]. It further protects CD4 T
cells from activation induced cell death (AICD) due to downregulation of FasL expression
again without an involvement of IL-2 [19,20]. Antigen specific CD4 T cells also expand more
vigorously in vivo when IL-6 is present during immunization due to reduced apoptosis
suggesting that IL-6 may increase the effector/memory T cell population [21]. Likewise, the
memory response against a second, heterologous influenza infection is impaired in IL-6 gene

deficient mice which coincides with reduced T cell numbers in the lung [22]. Interestingly,
IL-6 stimulation has been linked to increased migration of activated T cells in vitro [23] which
could explain their inability to enter the infected lungs in the absence of IL-6 during an
infection. In the light of recent findings regarding the role of IL-6 in T cell differentiation it
may be interesting to revisit the effects of IL-6 on CD4 T cell survival and correlate it to the
different T helper subsets generated in the presence of IL-6.
IL-6 in the Th1/Th2 decision

Since IL-6 is rapidly produced by professional APCs in response to different stimuli it was
possible that it may act similar to IL-12 in determining the differentiation of naïve CD4 T cells
in effector cells. Our group was the first to show that indeed IL-6 can modulate the Th1/Th2
balance towards Th2 [24]. IL-6 present during antigen stimulation of CD4 T cells promotes
autocrine IL-4 production which further enhances Th2 differentiation through an auto-
feedback loop [24](Fig. 1). The IL-6 mediated IL-4 expression requires upregulation of Nuclear
Factor of Activated T cells (NFAT)c2 expression which is largely absent in unstimulated naïve
CD4 T cells [25,26]. Nuclear accumulation of NFATc2 results in increased IL-4 expression.
It is unclear how IL-6 promotes NFATc2 expression but activation of C/EBP family members
is a likely mechanism as sequence analysis predicts potential C/EBP binding sites within the
NFATc2 promoter and C/EBP-mediated NFATc2 expression has been demonstrated in
hepatocytes [27]. In addition to NFATc2, IL-6 activates IL-4 expression through early
upregulation of the transcription factor c-maf in a STAT3 dependent pathway [28]. c-maf is
specifically expressed in Th2 cells and contributes to IL-4 expression via binding to its
promoter but is not required for IL-5 expression [29]. Interestingly, CD4 T cells differentiated
to Th2 in the presence of IL-6 are similarly unable to produce IL-5 although they express high
amounts of IL-4 [25]. How IL-6 orchestrates the effects of c-maf and NFATc2 has not been
addressed yet but the fact that c-maf alone is insufficient to mediate IL-4 expression suggests
a synergistic collaboration between both transcription factors. Given its enhancing effects on
Th2 differentiation, IL-6 may play a role in the development and exacerbation of Th2 mediated
diseases such as allergic airway inflammation and asthma. High IL-6 and sIL-6R levels have
been found in the bronchoalveolar lavage fluid of asthmatic patients as well as in mouse models
of allergic airway inflammation [30]. IL-6 has been suggested to play a protective role in
disease progression since IL-6 gene deficient mice exhibit increased inflammation compared
with their wild type littermates in a mouse model of allergic asthma [31]. On the other hand,
inhibition of IL-6R signaling by neutralizing antibodies against the IL-6R diminished disease
progression in a mouse model of OVA-induced allergic airway inflammation [32]. Although
it is not clear yet whether the IL-6 mediated effects in Th2-type diseases such as asthma are
through upregulation of IL-4 those results indicate that it could be a potential target for a
therapeutic intervention.
In addition to promote Th2 differentiation directly by upregulating IL-4 production, IL-6

contributes also in another, IL-4 independent way to Th2 differentiation of CD4 T cells. The
presence of IL-6 during the activation of CD4 T cells induces the expression of Silencer of
Cytokine Signaling (SOCS)1 thereby interfering with IFNγ signaling and production [33].
Without a positive feedback loop through endogenous IFNγ, CD4 T cells stimulated in the
presence of IL-6 produce less IFNγ and show a diminished Th1 phenotype. IL-6 has therefore
two independent ways to shift the Th1/Th2 balance of an immune response towards Th2, by
promoting early IL-4 expression and by rendering CD4 T cells unresponsive to IFNγ signals.
IL-6 in the regulation of Th17 differentiation

The effect of IL-6 on promoting Th2 and inhibiting Th1 differentiation does not correlate with
the high levels of IL-6 found in some autoimmune diseases such as rheumatoid arthritis which
had been associated with a Th1-type inflammatory response. This discrepancy was resolved

with the discovery of two new T cell subsets, T regulatory (Treg) and Th17 cells, which both
play a major role in inflammatory processes and are affected by IL-6 stimulation. Th17 cells
are a recently described subset of differentiated T effector cells which preferentially expresses
IL-17 while Th1 and Th2 cytokines are virtually absent in those cells [34]. Several studies have
now shown that the de novo differentiation of Th17 cells from naïve mouse CD4 T cells is
achieved by the simultaneous treatment with IL-6 and low doses of transforming growth factor
(TGF)β during antigen stimulation [35,36,37]. This function of IL-6 is completely dependant
upon TGFβ as IL-6 alone is unable to induce IL-17 expression. The contribution of TGFβ to
Th17 differentiation in human CD4 T cells remains controversial. Initial studies suggested that
a synergistic collaboration between IL-6 and IL-1β as well as IL-23 achieves Th17
differentiation while the presence of TGFβ was not required [38,39]. However, recent studies
have shown a requirement for low doses of TGFβ together with various combinations of
IL-1β, IL-6, IL-21, and IL-23 in Th17 differentiation of human naïve CD4 T cells [40,41,42].
Since IL-21 and IL-23 can induce STAT3 similar to IL-6 there may be some functional
redundancy between these cytokines which may explain why they all achieve IL-17 expression.
TGFβ has been known for a long time as an immunosuppressive cytokine and was described
to differentiate naïve CD4 T cells into inducible T regulatory (iTreg) cells [43]. As naturally
occurring Treg cells that arise in the thymus, iTreg express the transcription factor Foxp3 which
downmodulates IL-2 production and promotes immunosuppressive functions of Treg cells.
These studies now show a direct link between the differentiation of iTreg and Th17 cells
through the absence or presence of IL-6 during antigen stimulation. The first hint that IL-6
may play an important role in overcoming Treg mediated immune suppression was
demonstrated by a study showing that dendritic cells activated by toll-receptor stimulation
secrete cytokines that inhibit the Treg mediated suppression of activated T cells [44]. Further
analysis revealed that IL-6 was required for blocking Treg function although it was suggested
that it has to work in conjunction with some other cytokine(s) as its sole presence could not
abrogate the negative regulatory effect of Treg cells [44]. Likewise, transsignaling via the
soluble IL-6 receptor abrogates the induction of Foxp3 and the generation of iTreg in naïve
CD4 T cells through upregulation of the TGFβ signaling inhibitor Smad7 [45]. Thus, IL-6 has
a pivotal role in switching the immune response from a tolerant state to active inflammatory
conditions.
In several recent studies, the mechanisms by which IL-6 promotes Th17 differentiation have
been further elucidated. IL-6 together with TGFβ upregulates expression of the transcription
factor retinoic-acid receptor related orphan nuclear receptor (ROR)γt which is required for
IL-17 expression and has been postulated as Th17 lineage determining transcription factor
similar to T-bet for Th1 and c-maf and GATA3 for Th2 cells [46]. RORα is a close homologue
to RORγt and may play a similar role in Th17 differentiation [47]. It has been shown recently
that RORγt binds to a consensus motif in the IL-17 promoter but a direct interaction with Foxp3
inhibits its transcriptional activity [48]. IL-6 upregulates RORγt expression through STAT3
and downregulates Foxp3 thereby shifting the balance from Treg towards Th17 differentiation.
IL-6 promoting IL-21 production

In an effort to determine IL-6 induced changes in gene expression early upon antigen
stimulation of CD4 T cells we found that among many genes affected by the IL-6 treatment
the cytokine IL-21 was the only gene upregulated over 200-fold by IL-6 (Dienz, O.,
unpublished data). IL-21 is a common γ-chain dependant cytokine whose expression is
restricted to CD4 T cells and natural killer (NK)T cells [49,50]. It was first described as a
cytokine produced primarily by effector T cells, especially Th2 cells, but not by naïve CD4 T
cells [51]. However, our recent studies show that IL-21 can be readily produced by naïve and
memory CD4 T cells when IL-6 is present during antigen stimulation (Dienz, O., unpublished

data). No other cytokine appears to have an effect similar to IL-6. Recent studies have shown
that Th17 cells are high producers of IL-21 [52,53,54] and it is now believed to be a cytokine
specific for this T cell subset. However, the high production of IL-21 in Th17 cells could just
be the result of the presence of IL-6 during their differentiation. The fact that IL-6 induces
IL-21 expression prior to IL-17 expression and does not require the presence of TGFβ supports
this alternative model (Dienz, O., unpublished data). Furthermore, intracellular cytokine stain
of Th17 cells revealed that only a small percentage of cells co-express IL-17 and IL-21 while
the majority produces only one of the two cytokines (Dienz, O., unpublished data and [55]).
In addition, a recent study has shown that vasoactive intestinal peptide (VIP) together with
TGFβ induces the generation of Th17 cells that produce IL-17 and IL-22, but lack IL-21
expression [56]. Thus, IL-21 production appears to be dissociated from IL-17 production and
is highly dependant upon IL-6 stimulation. The induction of IL-21 expression in CD4 T cells
by IL-6 is independent of RORγt but requires binding of STAT3 to the IL-21 promoter [52,
57](Fig. 2). Initial studies proposed IL-21 as an autocrine factor further enhancing Th17
differentiation since it can promote IL-17 expression in the presence of TGFβ [52,53,54].
However, more recent studies show no requirement for IL-21 in mouse models of Th17-
associated diseases challenging the perception of IL-21 as a Th17 cytokine [58,59]. Thus, IL-21
may have some contribution to Th17 differentiation especially in vitro but other factors such
as IL-6 seem to play a much more important role in vivo. Whether IL-21 mediates some of the
effector functions of Th17 cells in certain diseases has become even more questionable when
there is only little overlap in the expression of IL-17 and IL-21. In summary, the combination
of IL-6 and TGFβ remains pivotal for the de novo differentiation of Th17 at least in mice.
Does IL-6 promote the differentiation of a unique T helper subset?

While IL-6 in the presence of TGFβ can generate Th17 cells, IL-6 by itself is also capable of
inducing additional types of effector cytokines and suppressing the production of others. The
question remains whether these CD4 T cells activated in the presence of IL-6 represent a
different subset from the currently well established Th1, Th2, and Th17 cells. Only recently,
a new CD4 T cell subset has been defined providing B cell help in germinal centers of B cell
follicles and therefore aptly termed T follicular helper (Tfh) cells [60]. They are characterized
by the expression of the chemokine receptor CXCR5 whose ligand CXCL13 is expressed by
lymphoid stromal cells attracting Tfh cells to lymphoid follicles [60]. Microarray analysis
revealed a very distinct gene expression profile of Tfh cells compared with Th1 and Th2
differentiated effector cells with IL-21 being a characteristic Tfh cytokine [61]. IL-21 is most
likely the main effector molecule of Tfh cells to mediate the generation of plasma cells and
antibody production in germinal center B cells. On the other hand, the factor(s) promoting the
Tfh phenotype have not been discovered yet. Since IL-6 is a major inducer of IL-21 production
in CD4 T cells it is possible that IL-6 contributes to the differentiation of the Tfh subset. This
model is supported by the fact that IL-6 differentiated effector cells retain their ability to
produce IL-21 even when cultured under Th1, Th2 or Th17 conditions [55]. Although IL-6 has
been initially described as B cell growth factor and has long been known to play a role in
antibody production this might be a mostly indirect effect through its upregulation of IL-21
production in CD4 T cells.
Conclusions
From its discovery as a B cell growth factor more than 20 years ago, our knowledge about the
functions of IL-6 has improved greatly. IL-6 is now considered as an important mediator of
the immune response especially by directly acting on CD4 T cells and determining their effector
functions. It remains an open question how IL-6 orchestrates all these different functions but
the presence of other factors will probably be a likely explanation. While TGFβ alone induces
Treg differentiation, IL-6 reduces Foxp3 expression and enhances RORγt expression, thereby

generating Th17 cells [48]. Thus, IL-6 is an important switch determining whether Th17 or
Treg cells are generated when TGFβ is present. Since IL-6 alone already upregulates the
expression of RORγt [52] the lack of IL-17 expression in IL-6 stimulated CD4 T cells suggests
that another critical signal is provided by TGFβ to achieve Th17 differentiation. Accordingly,
IL-6 generated effector cells are distinct from Th17 cells as they express high levels of IL-21
but not IL-17 [55]. IL-21 is the signature cytokine of Tfh cells suggesting a role of IL-6 in the
differentiation of this T helper cell subset but that remains to be further investigated [60]. IL-6
has also been reported to promote Th2 differentiation [24,25] and at first it seems difficult to
imagine how IL-6 stimulation could mediate the generation of two distinct T cell subsets.
Nevertheless, full differentiation of Tfh cells could require an additional signal which may be
provided by germinal center B cells or follicular dendritic cells which are in close contact to
Tfh cells during an immune response [60]. Another possibility is a linear model where IL-6
induced potential Tfh cells are an intermediate step in the differentiation of Th2 cells. In support
of such a model, IL-6 promotes IL-21 production before IL-4 can be detected and IL-6 induced
effector cells co-express both cytokines when exposed to Th2 conditions similar to IL-4
differentiated Th2 cells [25,55](Fig. 3). A further characterization of Tfh cells is necessary to
reveal their relationship to Th2 cells and how IL-6 affects their differentiation. Since both
subsets are thought to play an important role in providing B cell help an understanding of their
generation and maintenance may help in the design of efficient vaccines to promote long-
lasting protective antibody production.
Given the various responses elicited by IL-6 in CD4 T cells, therapies using humanized
antibodies against the IL-6R yielded promising results in several diseases so far. In fact, anti-
IL-6R therapy has already been approved in some countries for Castleman’s disease and shows
very good responses in clinical trials for rheumatoid arthritis and Crohn’s disease [2]. Since
Th17 cells are thought to play a major role in other autoimmune diseases such as multiple
sclerosis and psoriasis additional clinical applications for an anti-IL6 therapy may be worth
testing in the future, given the important role of IL-6 in Th17 differentiation. In addition, the
various ways of IL-6 in contributing to CD4 T cell effector functions suggests that other, more
Th2-type diseases like allergic asthma may benefit from a therapy targeting IL-6. One future
emphasis will be to define the molecular mechanisms of how exactly IL-6 contributes to disease
progression and CD4 T helper cell differentiation in various diseases. Although much progress
has been made lately in revealing the importance of IL-6 in CD4 T cell functions, there is still
more to be learned until the diverse functions of IL-6 in the immune response are understood.
Acknowledgements
This work was supported by NIH grant P01AI045666 (M. R.).
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Figure 1.
Molecular mechanism of IL-6 induced IL-4 production. Stimulation by IL-6 activates the
transcription factors STAT3 through JAKs and C/EBP through the ras-ERK MAPK cascade.
STAT3 upregulates c-maf expression while C/EBP may mediate upregulation of NFATc2. c-
maf and NFATc2 activate in a potentially synergistic manner the expression of IL-4. Autocrine
production of IL-4 will subsequently promote Th2 differentiation.

Figure 2.
IL-6 exerts its effects on cytokine production through a diverse set of key molecules.
Upregulation of SOCS1 expression inhibits IFNγ signals thereby diminishing additional
IFNγ production. IL-4 production is mediated through the induction of NFATc2 and c-maf
expression. STAT3 directly regulates IL-6 induced IL-21 expression, which therefore precedes
expression of the other cytokines. Simultaneous stimulation through IL-6 and TGFβ induces
high level expression of RORγt which mediates IL-17 production.

Figure 3.
Contribution of IL-6 to T helper cell differentiation and subsequent cytokine production by
various T cell subsets. IL-6 exerts inhibitory activity towards Th1 and T regulatory (Treg)
differentiation/function and promotes Th2 and Th17 differentiation either alone (Th2) or
together with TGFβ (Th17). The role of IL-6 in T follicular helper (Tfh) cell differentiation is
suggested due to its specific upregulation of IL-21 in naïve CD4 T cells.

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Clin Immunol. 2009 January ; 130(1): 27–33. doi:10.1016/j.clim.2008.08.018.

The effects of IL-6 on CD4 T cell responses

Oliver Dienz* and Mercedes Rincon*

The IL-6 receptor and its signaling pathways

IL-6 in T cell survival and proliferation

Clin Immunol. Author manuscript; available in PMC 2010 January 1.

IL-6 in the Th1/Th2 decision

In addition to promote Th2 differentiation directly by upregulating IL-4 production, IL-6

IL-6 in the regulation of Th17 differentiation

Clin Immunol. Author manuscript; available in PMC 2010 January 1.

IL-6 promoting IL-21 production

Clin Immunol. Author manuscript; available in PMC 2010 January 1.

Does IL-6 promote the differentiation of a unique T helper subset?

Clin Immunol. Author manuscript; available in PMC 2010 January 1.

Clin Immunol. Author manuscript; available in PMC 2010 January 1.

Clin Immunol. Author manuscript; available in PMC 2010 January 1.

Clin Immunol. Author manuscript; available in PMC 2010 January 1.

48. Ichiyama K, Yoshida H, Wakabayashi Y, Chinen T, Saeki K, Nakaya M, Takaesu G, Hori S,

Clin Immunol. Author manuscript; available in PMC 2010 January 1.

Clin Immunol. Author manuscript; available in PMC 2010 January 1.

Clin Immunol. Author manuscript; available in PMC 2010 January 1.

Clin Immunol. Author manuscript; available in PMC 2010 January 1.

Clin Immunol. Author manuscript; available in PMC 2010 January 1.

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