IL-17 and Th17 Cells

ANRV371-IY27-18 ARI 16 February 2009 12:37
IL-17 and Th17 Cells

ANNUAL
REVIEWS Further Thomas Korn,1 Estelle Bettelli,2 Mohamed Oukka,3
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Annu. Rev. Immunol. 2009.27:485-517. Downloaded from arjournals.annualreviews.org
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Annu. Rev. Immunol. 2009. 27:485–517 Key Words

First published online as a Review in Advance on T cell differentiation, effector T cells, regulatory T cells, cytokines,
January 8, 2009
tissue inflammation, autoimmunity
The Annual Review of Immunology is online at
immunol.annualreviews.org Abstract
This article’s doi: CD4+ T cells, upon activation and expansion, develop into different
10.1146/annurev.immunol.021908.132710
T helper cell subsets with different cytokine profiles and distinct ef-
Copyright c 2009 by Annual Reviews. fector functions. Until recently, T cells were divided into Th1 or Th2
All rights reserved
cells, depending on the cytokines they produce. A third subset of IL-
0732-0582/09/0423-0485$20.00 17-producing effector T helper cells, called Th17 cells, has now been
discovered and characterized. Here, we summarize the current informa-
tion on the differentiation and effector functions of the Th17 lineage.
Th17 cells produce IL-17, IL-17F, and IL-22, thereby inducing a mas-
sive tissue reaction owing to the broad distribution of the IL-17 and
IL-22 receptors. Th17 cells also secrete IL-21 to communicate with
the cells of the immune system. The differentiation factors (TGF-β
plus IL-6 or IL-21), the growth and stabilization factor (IL-23), and the
transcription factors (STAT3, RORγt, and RORα) involved in the de-
velopment of Th17 cells have just been identified. The participation of
TGF-β in the differentiation of Th17 cells places the Th17 lineage in
close relationship with CD4+ CD25+ Foxp3+ regulatory T cells (Tregs),
as TGF-β also induces differentiation of naive T cells into Foxp3+ Tregs
in the peripheral immune compartment. The investigation of the differ-
entiation, effector function, and regulation of Th17 cells has opened up
a new framework for understanding T cell differentiation. Furthermore,
we now appreciate the importance of Th17 cells in clearing pathogens
during host defense reactions and in inducing tissue inflammation in
autoimmune disease.
485
INTRODUCTION human inflammatory conditions. In the past

+ five years, we have witnessed an accumulation
The differentiation of naive CD4 T cells into
of information on this new T cell subset: The
effector T helper cells is initiated by engage-
cytokines for its differentiation and expansion
ment of their T cell receptor (TCR) (signal 1)
have been identified (2–9) and the key transcrip-
and costimulatory molecules (signal 2) in the
tion factors that are involved in its generation
presence of specific cytokines produced by the
have been elucidated (10, 11), firmly establish-
innate immune system upon encounter of par-
ing Th17 cells as an independent T helper cell
ticular pathogens: IFN-γ and IL-12 initiate the
lineage in human and mouse.
differentiation of Th1 cells that are character-
Here, we review the findings that led to the
ized by high production of IFN-γ and are indis-
identification of Th17 cells and integrate the
pensable for clearing intracellular pathogens.
current knowledge on their differentiation and
In contrast, IL-4 triggers the differentiation of
effector functions. The requirement of TGF-
Th2 cells. Th2 cells are key in organizing host

β in combination with other cytokines for the

defense against extracellular pathogens and in
differentiation of Th17 cells and other T cell
helping B cells to produce antibodies. The ini-
subsets is a unique new concept that opens up
tial source of the differentiation factors for both
new views on the generation of T helper cell
Th1 and Th2 cells are cells of the innate im-
subsets in the peripheral immune compartment
mune system responding to microbial antigens,
and underscores potential developmental rela-
parasitic antigens, or allergens; however, the
tionships between various T cell subsets that
effector cytokines that are subsequently pro-
were not anticipated. In addition, many ques-
duced by Th1 and Th2 cells (i.e., IFN-γ and
tions of lineage stability versus plasticity of dif-
IL-4) can potentially feed back to amplify Th1
ferentiated Th17 cells in vivo are as yet un-
and Th2 cells and further enhance differentia-
resolved. Most importantly, although we have
tion of the respective T cell subset. Moreover,
learned much about the differentiation and sta-
IFN-γ and IL-4 antagonize each other on dif-
bilization of Th17 cells, there is still uncertainty
ferent levels, and thus Th1 and Th2 develop-
about their effector function in vivo. Given that
ment is considered mutually exclusive. Thus,
Th17 cells secrete not only IL-17 but also IL-
even though the cytokine profile may initially
17F, IL-21, and IL-22, these cytokines most
not be entirely polarized with differentiating
likely cooperate to induce tissue inflammation,
T cells producing a combination of both Th1
and Th17-driven effector functions may be dif-
and Th2 cytokines, chronic stimulation leads to
ferent in different tissues. Conversely, Th17
unequivocal, terminally differentiated pheno-
cells are not the only source of IL-17, but rather
types. Over the years, this Th1/Th2 paradigm
other cells of the innate immune system can
of T helper cell differentiation, which was first
produce IL-17, IL-17F, and IL-22. Moreover,
introduced by Mosmann & Coffman (1) about
we do not know whether Th17 cells have to co-
25 years ago, helped explain many phenomena
operate with other effector T helper cells such
in adaptive immunity. Recently, the Th1/Th2
as Th1 cells to display their full effector func-
paradigm has been expanded, following the dis-
tions, and finally, we have only limited infor-
covery of a third subset of effector Th cells
mation on the termination of Th17 responses,
that produce IL-17 (Th17) and exhibit effector
specifically whether Th17 responses can be ef-
functions distinct from Th1 and Th2 cells. The
fectively controlled by Tregs.
primary function of Th17 cells appears to be the
clearance of pathogens that are not adequately
handled by Th1 or Th2 cells. However, Th17 INITIAL IDENTIFICATION OF
cells are potent inducers of tissue inflammation Th17 CELLS
and have been associated with the pathogenesis Dysregulated Th1 responses have been as-
of many experimental autoimmune diseases and sociated with organ-specific autoimmunity.
486 Korn et al.

IFN-γ expression in the target tissues correlates helper cell subset, which was named Th17 cells
with clinical signs in experimental autoimmune (9, 18, 19). However, in view of the fact that
encephalomyelitis (EAE) and collagen-induced the IL-23 receptor is not expressed on naive T
arthritis (CIA). Self-reactive Th1 clones de- cells, and, in our hands, IL-23 was not able to
rived in vitro are capable of adoptively trans- generate de novo IL-17-producing T cells from
ferring EAE in naive recipients. T-bet- and sorted naive T cells (3), this raised the issue of
STAT4-deficient mice are resistant to EAE, whether IL-23 indeed is the differentiation fac-
and targeting IL-12 with polyclonal antibod- tor of Th17 cells, and, if not, then what are the
ies to IL-12 is an efficient therapy for EAE and factors needed for the differentiation of Th17
CIA. These findings led to the idea that IFN- cells.
γ-producing Th1 cells with specificity for self-
antigens are autopathogenic and required for
the induction of organ-specific autoimmunity. DIFFERENTIATION OF
Th17 CELLS
However, the concept that organ-specific au-

toimmunity is a Th1-driven condition was chal- Th17 cells were established as an independent
lenged when it became clear that IFN-γ- and subset of T helper cells by the identification
IFN-γ receptor–deficient mice, as well as mice of differentiation factors and transcription
that lack other molecules involved in Th1 dif- factors that are unique to Th17 cells. In
ferentiation such as IL-12p35, IL-12 receptor- 2006, three independent studies found that
β2, and IL-18, were not protected from EAE, a combination of the immunoregulatory
but rather developed more severe disease (12– cytokine TGF-β and the proinflammatory
16). This raised the question of whether an- and pleiotropic cytokine IL-6 is required to
other subset of T cells, different from Th1 induce IL-17 in naive T cells (2–4) (Figure 1).
cells, might be required for the induction of We fortuitously identified TGF-β and IL-6
EAE and other organ-specific autoimmune as the differentiation factors for Th17 cells
diseases. while looking for the factors that inhibited the
In 2000, a novel cytokine chain, p19, was TGF-β-driven conversion of naive T cells into
discovered by a computational sequence screen Foxp3+ Tregs in vitro and in vivo. Using naive
looking for homologs of the IL-6 subfamily T cells from reporter mice that expressed the
of proteins (17). This p19 chain forms het- green fluorescent protein (GFP) targeted into
erodimers with the p40 chain of IL-12, and this the Foxp3 locus, the transcription factor for
novel cytokine was named IL-23; thus, all ap- Tregs, we screened a panel of cytokines and
proaches that targeted the p40 chain of IL-12 found not only that IL-6 is extremely potent
would affect both IL-12 and IL-23. By creat- in inhibiting the TGF-β-driven induction of
ing IL-23p19 knockout (KO) mice and com- Foxp3, but also that TGF-β together with
paring them with IL-12p35-deficient mice, Cua IL-6 induces massive amounts of IL-17 from
and colleagues (8) at the DNAX Research In- naive T cells. Given that we started with sorted
stitute demonstrated that IL-23 and not IL-12 naive (CD4+ CD62Lhigh CD25− Foxp3− ) T
was crucial for the induction of EAE. In the cells, we demonstrated that TGF-β plus IL-6
follow-up study (9), they showed that IL-23 together can differentiate naive T cells into the
expands/generates IL-17-producing T cells Th17 lineage. Interestingly, two cytokines with
that are capable of inducing EAE when adop- opposing effects have to cooperate to induce
tively transferred into naive wild-type mice. the differentiation of Th17 cells, suggesting
These IL-17-producing T cells were dramat- that signaling molecules and transcription fac-
ically reduced in the central nervous system tors involved downstream of the TGF-β and
(CNS) of IL-23p19-deficient mice. On the basis IL-6 receptors work together to induce Th17
of this and other studies, investigators proposed differentiation (see below). To support the role
that IL-17-producing T cells are a distinct T of TGF-β and IL-6 in Th17 differentiation
www.annualreviews.org • Th17 Cells 487

a b
Mouse Mouse
T naive TGF-β + IL-6 Th17 Innate immune cell
TGF-β + IL-21 IL-17
IL-17F
IL-21
CD4+CD25– Th17
CD62L+Foxp3– effector
T naive Th17 memory IL-17
IL-17F
T cell TGF-β IL-6 IL-23
activated IL-6
IL-17 IL-21
memory Th17 TNF
IL-23 IL-17F
IL-17 Integrin α3
IL-23 (+ IL-1β) IL-6
IL-17F IL-22
TNF
Integrin α3 IL-21
CD4+ IL-22
(in vivo primed)
or
CD4+CD44+
Human Human
T naive Th17 Innate immune cell

TGF-β + IL-21
IL-17
IL-17F
(IL-21)
Cord blood
CD4+CD25–
CD62L+CD45RA+
Th17
IL-17 effector IL-17
T naive Th17 T naive IL-1β Th17 memory IL-17F
TGF-β + IL-23 (+ IL1β/IL-6/TNF) IL-17F IL-6 IL-1β, IL-6,
TGF-β + IL-1β (+IL-6/IL-21/IL-23) IL-21 TGF-β IL-23 IL-1β, IL-23 IL-21
IL-22 IL-21 IL-22
IL-26 IL-26
Cord blood IL-17 CCL20
CCR6
CD4+CD25– IL-17F CCR6
CD45RO– (IL-21)
IL-1β + IL-6
(serum-containing medium)
T cell Th17 IL-17
IL-1β + IL-23
(serum-containing medium) IL-17F
IL-22
IL-26
PBMC CCL20
CD4+CD25–
CD45RA+CCR7+
or
CD4+CD45RO–
Figure 1
Differentiation of Th17 cells in mice and humans. (a) Factors required to induce the development of Th17 cells in mice starting from
naive T cells (light blue) or activated CD4+ T cells. In humans, different Th17 differentiation factors were initially reported. However,
when rigorously sorting for naive T cells as a starting population and controlling hidden sources of TGF-β in the culture conditions,
identical factors seem to induce Th17 cells in mouse and human (for details see text). IL-23 might be required to induce further effector
molecules in committed Th17 cells (purple) to establish their terminally differentiated effector phenotype (orange). (b) The sources of
Th17 differentiation factors have partially been revealed in vivo. Moreover, IL-21 feeds back on developing Th17 cells, amplifying
their frequency, as do IFN-γ and IL-4 in the differentiation of Th1 and Th2 cells, respectively.
488 Korn et al.

further, we found that TGF-β transgenic mice, tiate into Th17 cells upon exposure to TGF-β
which overexpress TGF-β under the IL-2 pro- plus IL-6 or TGF-β plus IL-21, the combina-
moter, had higher frequencies of Th17 cells and tions of IL-1β plus IL-6 (26) or IL-1β plus IL-
developed more severe EAE when immunized 23 (27) were proposed to be the differentiation
with myelin autoantigen in complete Freund’s factors for human Th17 cells. Thus, a rather
adjuvant (CFA). Because immunization with disturbing problem was raised by the claim that
CFA induces IL-6 from innate immune human Th17 cells could develop in the ab-
cells, we hypothesized that this CFA-driven sence of TGF-β, suggesting that the require-
IL-6 acted together with the transgenically ments for human and mouse Th17 differentia-
expressed TGF-β to induce Th17 cells in tion are essentially different. In these previous
vivo. These data suggested that IL-6 plays a human studies, naive T cells were selected from
pivotal role in dictating whether an immune human peripheral blood mononuclear cells ac-
response is dominated by Foxp3+ Tregs or cording to expression of CD45RA. The dif-
Th17 cells. ferentiation was performed in the presence of

On the basis of this observation, we pre- serum, and contamination with platelets (an im-
dicted that IL-6-deficient mice would lack the portant source of TGF-β), even if no exogenous
ability to generate Th17 cells and that their TGF-β was added, could not be excluded owing
repertoire would be dominated by Tregs. To to the experimental protocols used to isolate hu-
test this prediction, we retested IL-6 KO mice man T cells from peripheral blood. Thus, these
that had been described to be resistant to EAE results were difficult to interpret until human
(3, 20–23) and antigen-induced arthritis (24). T cell differentiation cultures were rigorously
We showed that Il6−/− mice had a defect in the sorted for naive T cells and sources of TGF-β
generation of Th17 cells and that the immune in serum and platelets were controlled. A series
response in these mice is indeed dominated of three new reports tackled these problems,
by Foxp3+ Tregs. However, upon depletion of proving that TGF-β is indeed essential for the
Tregs, IL-6 KO mice became susceptible to differentiation of human Th17 cells from naive
EAE owing to the appearance of a pathogenic T cells (28–30) as well. TGF-β is absolutely re-
Th17 response, raising the possibility that in quired to induce RORc (the human homolog
the absence of IL-6, another factor could in- of RORγt), but its expression and function are
duce Th17 cells (5). To identify this factor, we inhibited by excess TGF-β. Only when addi-
rescreened a panel of cytokines that, like IL- tional cytokines such as IL-6 plus IL-23 or IL-
6, suppressed the TGF-β-induced expression 21 are present is RORc relieved from inhibi-
of Foxp3 and induced IL-17 production. In tion, and then naive T cells can begin tran-
this screen, we identified IL-21, an IL-2 fam- scribing IL-17 (29). Thus, at a molecular level,
ily member, that both suppressed the TGF- the differentiation conditions of mouse and hu-
β-induced expression of Foxp3 and, together man Th17 cells do not appear to be different
with TGF-β, induced IL-17 in naive T cells (Figure 1).
(5). Because Th17 cells themselves are a ma-
jor source of IL-21, an autocrine amplification
loop was proposed by which Th17 cells en- ROLE OF TGF-β
hance their own differentiation and precursor TGF-β is a regulatory cytokine with
frequency (5–7, 25) (Figure 1). pleiotropic functions in T cell development,
As far as human T cells are concerned, the homeostasis, and tolerance (31). However,
situation for the differentiation of Th17 cells when T cells are deficient in a functional
has been confusing. In 2007, several studies receptor for TGF-β and thus cannot respond
claimed that TGF-β was dispensable for the to TGF-β, Th17 cells are not generated and
differentiation of human Th17 cells (26, 27). mice are protected from EAE (32). Conversely,
Whereas naive mouse CD4+ T cells differen- as discussed above, transgenic overexpression

of TGF-β by T cells resulted in more severe It remains to be determined whether other

EAE with enhanced Th17 generation when the effector cytokines produced by Th17 cells are
TGF-β transgenic mice were immunized with differentially regulated by TGF-β. For exam-
myelin oligodendrocyte glycoprotein in CFA ple, IL-22, which is also produced by Th17
(3). Given that TGF-β is produced by multiple cells, appears to be less dependent on TGF-β.
lineages of leukocytes and stromal cells, it has In an antigen-presenting cell (APC)-free sys-
been very difficult to define the sources of tem, in a starting population of naive T cells,
TGF-β that are relevant for the generation of maximal amounts of IL-22 were induced by
Th17 cells in vivo. In a recent study, Flavell TCR stimulation in the presence of IL-6 alone,
and coworkers (33) generated mice with a and titration of TGF-β increasingly inhibited
disrupted TGF-β1 gene only in T cells. the secretion of IL-22. However, IL-22 is not
These mice developed a lethal inflammatory exclusively produced by Th17 cells, but rather
disorder characterized by enhanced Th1 and appears to be produced by activated T cells in
Th2 responses, indicating that Treg-derived general, as well as by IL-2- or IL-12-stimulated

TGF-β is required to control exaggerated Th1 natural killer (NK) cells (36). IL-6 together with
and Th2 responses. Interestingly, ablation of TGF-β is crucial for the generation of Th17
TGF-β production from T cells also resulted cells, considering that IL-6 alone cannot in-
in a defect in the generation of Th17 cells duce RORγt (the transcription factor involved
and the development of EAE (33). This study in the induction of Th17 cells; see below), and
suggested that an autocrine or paracrine source Th17 cells are not induced. TGF-β is abso-
of TGF-β was important for Th17 differen- lutely required both for the initial induction of
tiation in vivo. Thus, T cells and even Tregs IL-17 in naive CD4+ T cells and for the in-
themselves (2) may be the source of TGF-β duction of IL-23R, which makes differentiating
for the differentiation of Th17 cells; in support Th17 cells responsive to IL-23 and therefore
of this idea, it was shown that transfer of naive further promotes their maturation. However,
T cells together with Tregs into recipient mice high concentrations of TGF-β inhibit the ex-
promoted the induction of IL-17 but not of pression of IL-23R, suggesting a biphasic effect.
IFN-γ in the cotransferred conventional T When Th17 cells are induced in an APC-free
cells (34). TGF-β is produced in its latent form system by the combination of TGF-β plus IL-
and needs to be activated. This is achieved 6 (in the absence of any additional exogenous
either by proteolytic degradation or by confor- cytokines), IL-22 production is essentially ab-
mational changes of latency-associated protein sent. Th17 cells that have been induced with
(LAP), which is associated with TGF-β in TGF-β plus IL-6 do not produce IL-22 unless
a heterotetrameric form and constrains the they have been exposed to IL-23. Thus, Th17-
binding of the TGF-β homodimer to its derived IL-22 is dependent on IL-23 and ap-
receptor. For example, binding of LAP to pears to be a Th17 cytokine that is associated
thrombospondin on vascular endothelium or with a terminal differentiation stage of Th17
to integrins αv β6 on epithelial cells or αv β8 on cells. Collectively, TGF-β is indispensable for
dendritic cells (DCs) results in processing of the generation of Th17 cells, although high
LAP and activation of TGF-β in vivo. In fact, concentrations of TGF-β may inhibit the pro-
when αv β8 is conditionally deleted in DCs, duction of various effector cytokines of Th17
the mice suffer from a lymphoproliferative cells and ultimately inhibit the generation of
syndrome and tissue inflammation that is Th17 cells by inducing Foxp3. This scenario
reminiscent of TGF-β deficiency in T cells might seem confusing at first, but it fits with the
(35). Thus, it is believed that DCs, though not observation that Th17 cells and induced Tregs
primary producers of TGF-β, are essential to share common developmental pathways, where
raising the levels of active TGF-β in the local TGF-β has been clearly recognized as a link
environment. between these two T cell subsets.
490 Korn et al.

ROLE OF IL-6 sion of IL-6Rα, TCR stimulation as well as

Like TGF-β, IL-6 has a plethora of activities exposure to IL-6 lead to downregulation and
outside the immune and even hematopoietic shedding of the IL-6Rα and thus reduce re-
systems and is clearly a pleiotropic cytokine sponsiveness to IL-6. TGF-β is necessary to
with multiple effects. IL-6 is produced by cells maintain the responsiveness of T cells to IL-6.
of the innate immune system such as DCs, Second, engagement of the IL-6 receptor and
monocytes, macrophages, mast cells, B cells, activation of gp130 lead to activation of STAT3.
and subsets of activated T cells, but also by tu- Activation of STAT3 is necessary but not suffi-
mor cells, fibroblasts, endothelial cells, and ker- cient to induce RORγt. Deficiency of STAT3
atinocytes (for review, see 37, 38). Production in T cells abrogates the induction of Th17
of IL-6 is part of the acute-phase response dur- cells and decreases the induction of RORγt
ing infection, and, apart from its originally dis- and RORα (11, 41), two transcription factors
involved in Th17 differentiation. Accordingly,
covered properties as a myeloma growth factor,

IL-6 is also a hepatocyte-stimulating factor, re- mice with conditional deficiency of STAT3 in
sulting in the production of a number of acute- CD4+ T cells lack antigen-specific Th17 re-
phase proteins by hepatocytes. Depending on sponses and are resistant to EAE (42). IL-6-
the cellular source of IL-6, cytokines such as driven STAT3 signaling is required for RORγt
IL-1, tumor necrosis factor (TNF), platelet- function. However, full induction of RORγt is
derived growth factor (PDGF), IL-3, GM- only achieved in the presence of TGF-β. Re-
CSF, and IL-17 are important inducers of IL-6 cent studies suggest the TGF-β promotes the
(39, 40). expression of RORγt but represses its func-
Different approaches led to the identification (43). Only the additional presence of IL-
tion of IL-6 as an essential differentiation factor 6 or IL-21 signaling relieves the repression of
for Th17 cells. In an APC-free culture system RORγt and promotes the Th17 transcriptional
of naive T cells, where supernatant from LPS- program (29, 43).
stimulated DCs was used together with TGF-
β, the differentiation of Th17 cells could be
completely abolished by addition of an antibody ROLE OF IL-21
to IL-6 (2). We found that addition of recombi- IL-21 is a cytokine that was first identified in
nant IL-6 was extremely potent in suppressing 2000 by Parrish-Novak and colleagues (44). It
the TGF-β-driven induction of Foxp3 in naive is produced by activated T cells and NKT cells,
T cells and instead resulted in strong induction but not by APCs (44). IL-21 belongs to the IL-
of IL-17 (3). 2 family of cytokines and uses the common γ
TGF-β alone via activation of the Smad chain (γc ) as part of its receptor consisting of
pathway induces genes involved in downregu- γc plus IL-21R. IL-21 has been described as
lation of immune responses, IL-6 alone leads playing an important part in the expansion of
to strong but transient activation of STAT3, previously activated B cells and in class switch-
yet when TGF-β and IL-6 were added simul- ing of immunoglobulin isotypes (45). IL-21 is
taneously, they induced a distinct transcrip- abundantly expressed in certain populations of
tional program resulting in the development T cells, e.g., in T follicular helper cells (46) that
of Th17 cells. Mechanistically, the interaction express high levels of CXCR5 and ICOS (47).
of TGF-β and IL-6 in inducing the Th17 IL-21 is also produced by Th2 cells (48), but
transcriptional program is incompletely under- comparing the Th1, Th2, and Th17 subsets,
stood. First, naive T cells express a functional the largest amounts of IL-21 are produced by
IL-6 receptor composed of IL-6Rα and the sig- Th17 cells (5, 6). IL-6 is a strong inducer of IL-
naling subunit gp130, which is constitutively 21 (49), and the expression of IL-21 is depen-
expressed. While TGF-β induces the expres- dent on STAT3 but not on RORγt, as RORγt

KO mice express normal levels of IL-21 (7). nization with autoantigen emulsified in CFA),
IL-21 together with TGF-β is able to induce IL-21 is dispensable, and Th17 cells can be in-
the differentiation of Th17 cells. Thus, IL-21 duced and maintained even in the absence of
produced by differentiating Th17 cells might IL-21 (53, 54). Thus, we proposed that IL-21
act in a positive feedback loop, amplifying the constitutes an alternative pathway for inducing
precursor frequency of Th17 cells (5–7). This is Th17 cells that is followed only when there is
intriguing, as autoamplification loops have been no induction of IL-6 and when Treg cells have
described for both Th1 and Th2 cells, in which been deleted from the peripheral repertoire (5).
the effector cytokines IFN-γ and IL-4 also act Under these circumstances, IL-21 is essential
as the amplification factors for Th1 and Th2 in inducing and expanding Th17 cells. In vivo,
cells, respectively. IL-17 cannot amplify Th17 however, IL-6 appears to be dominant over IL-
cells because IL-17 does not act as a growth or 21, and when excess IL-6 is induced by immu-
differentiation factor for the Th17 lineage. In nization with myelin antigen in CFA (53, 54),
view of the fact that differentiating Th17 cells the requirement for IL-21 in the induction of
produce maximum levels of IL-21, we and oth- Th17 cells is overcome owing to excessive and
ers have proposed that IL-21 produced by dif- continuous IL-6 production by the peripheral
ferentiating Th17 cells might play this role in immune system. That IL-21 is an alternative
amplifying the frequency of Th17 cells (5–7). pathway is consistent with our observation that
The relative impact of IL-6 and IL-21 in although IL-21 is induced by and is downstream
the differentiation of Th17 cells in vivo is not of IL-6, IL-6 and TGF-β together are able to
yet entirely clear. Both TGF-β plus IL-6 and induce Th17 cells independently of IL-21 sig-
TGF-β plus IL-21 induce the expression of naling. This interpretation of our data is not at
RORγt, which is necessary and sufficient to odds with the finding that Th17 cells and EAE
trigger the expression of IL-23R. In turn, IL-23 can be induced in Il21−/− mice by immunizing
stabilizes the commitment of developing Th17 these mice with myelin antigen in CFA (53–55)
cells to the Th17 lineage (7). However, in vivo as in such a case massive amounts of IL-6 are
IL-6 plays a dominant role in Th17 differen- produced, thus overcoming the need for IL-21
tiation, and only in the absence of IL-6 and to amplify the Th17 response.
following depletion of Tregs did we observe a
role for IL-21 in inducing Th17 cells. More-
over, we proposed that in the absence of in- TRANSCRIPTION FACTORS
flammation, when the levels of IL-6 are not el- INVOLVED IN Th17
evated, IL-21 might play a role in maintaining DIFFERENTIATION
the precursor pool of Th17 cells, as the fre- The differentiation of T helper cells is initiated
quency of Th17 cells in the memory T cell by the combined signals mediated downstream
pool was reduced in IL-21R KO mice (5). Thus, of the TCR and cytokine receptors. Those sig-
IL-21, which is produced by Th17 cells them- nals then induce and activate specific transcrip-
selves (5, 6, 25), helps to maintain and amplify tion factors responsible for the expression of
the pool of Th17 precursors when the supply lineage-specific genes such as cytokines. The
of IL-6 is limited. Under these circumstances, engagement of the TCR is able to induce the
IL-21 might become important for support- expression of T-bet or GATA-3, transcription
ing Th17 responses and tissue inflammation. factors specifically and respectively expressed in
Several studies suggest that this is indeed the Th1 and Th2 cells. GATA-3, on the one hand,
case in, for example, autoimmune diabetes or is essential for Th2 cell lineage commitment
chronic inflammatory bowel disease (50–52), in and induces the expression of IL-4. T-bet, on
which IL-21 plays an important role in inducing the other hand, can bind to the IFN-γ promoter
autoimmunity. In contrast, in the presence of and induces the expression of this cytokine. The
massive amounts of IL-6 (as induced by immu- sustained production of effector cytokines and
492 Korn et al.

subsequent differentiation of Th cell subsets Mice with conditional deficiency of STAT3

requires the engagement of specific cytokines in T cells have impaired Th17 differentiation,
with their receptors. For Th1 cells, the engage- and overexpression of a constitutively active
ment of IFN-γ with its receptor leads to the form of STAT3 can increase IL-17 production
activation of STAT1 and T-bet. In turn, T-bet (11, 42). Thus, STAT3 might affect the expres-
increases the production of IFN-γ and induces sion of IL-17 by increasing the expression of
the expression of the inducible IL-12Rβ2 chain RORγt and RORα, which are upstream of IL-
of the IL-12R. IL-12, through STAT4, is then 17 (11, 41). However, STAT3 also binds di-
essential for the maintenance of Th1 responses. rectly to the Il17 and Il21 promoters (25, 58).
For Th2 cells, the interaction of IL-4 with its Therefore, STAT3 and RORγt seem also to
receptor activates STAT6, which together with cooperate, and competent production of IL-17
GATA-3 increases IL-4 production and Th2 depends on the presence of both transcription
commitment. factors.
The steroid receptor–type nuclear receptor RORγt likely must cooperate with other
RORγt, which is a splice variant of RORγ ex- as yet unidentified transcription factors in the
pressed in T cells (56, 57), is selectively ex- induction of Th17 cells. For example, the
pressed in in vitro–differentiated Th17 cells interferon regulatory factor 4 (IRF4), which
and in IL-17+ T cells present in the lamina was previously associated with the differenti-
propria of naive mice (10). RORγt appears to ation of the Th1 and Th2 subsets (61, 62),
be required for IL-17 production, as mice re- is required for the differentiation of Th17
constituted with the bone marrow of RORγt- cells as well (63). IRF4 KO mice failed to
deficient mice show an impaired Th17 differ- mount a Th17 response and were resistant to
entiation (10). Furthermore, transduction of EAE. Consistent with this observation, IRF4-
naive T cells with a retroviral vector contain- deficient T cells failed to upregulate RORγt
ing RORγt induces the development of IL- upon stimulation in the presence of TGF-
17-producing T cells (10). However, although β plus IL-6 and could not be differentiated
reduced, IL-17-producing cells are not absent into Th17 cells (63). However, overexpres-
in RORγt-deficient mice. Another member of sion of RORγt in IRF4-deficient T cells failed
the retinoid nuclear receptor family, RORα, is to fully restore the induction of IL-17, again
also selectively expressed in Th17 cells—very suggesting that IRF4 or its downstream tar-
similarly to RORγt. A recent study reported gets may have to cooperate with RORγt for
that RORα could fulfill a similar but not iden- full commitment of T cells to the Th17
tical role to RORγt in the differentiation of lineage.
Th17 cells, suggesting that Th17 cell differen-
tiation could be dictated by two lineage-specific
transcription factors (41). However, the mech- RECIPROCAL RELATIONSHIP
anisms by which RORγt and possibly RORα BETWEEN Th17 CELLS
regulate IL-17 production have not yet been AND TREGS
fully elucidated. Although there is a potential Th17 and Treg developmental programs of T
ROR-binding site in the IL-17 promoter, it is cells are reciprocally interconnected. This dis-
not clear whether RORγt binds directly to this covery was initially based on the observation
promoter. RORγt and RORα are both strongly that upon TCR stimulation, a naive T cell can
induced by IL-6 or IL-21 in the presence of low be driven to express Foxp3 and become a Treg
amounts of TGF-β. The induction of RORγt cell in the presence of TGF-β. However, in
is dependent on STAT3, which is preferentially the presence of TGF-β plus IL-6 or IL-21, the
activated by IL-6, IL-21, and IL-23 and plays Treg developmental pathway is abrogated, and
an important role in the regulation of IL-17 instead T cells develop into Th17 cells. Only
production in T cells (7, 11, 58–60). the combination of TGF-β plus IL-6/IL-21,

but neither of them alone, induced robust pro- tion of Foxp3, it is probably dispensable for
duction of IL-17 in naive T cells. the induction of RORγt (66). In the presence
In vitro, there is a true reciprocity between of TGF-β, IL-6 and IL-21 play an important
the Th17 and Treg developmental programs on role in Th17 differentiation by inhibiting TGF-
the single-cell level. However, evidence is still β-driven Foxp3 expression. Both RORγt and
incomplete as to whether this reciprocal devel- RORα physically associate with Foxp3 to an-
opmental decision at the single-cell level is also tagonize each other’s functions (43, 67). This as-
relevant in vivo. Active TGF-β is a cytokine sociation is likely the molecular basis for the re-
produced by various cell types, including nat- ciprocal relationship between Tregs and Th17
ural Treg cells (nTreg) and cells of the innate cells. Foxp3 binds to RORγt via a motif ex-
immune system. TGF-β has broad inhibitory pressed in exon 2. When Foxp3 lacks exon 2,
effects on the entire immune system (for re- the binding to RORγt is abolished and the
view, see 31). In addition, TGF-β induces the Foxp3-mediated inhibition of RORγt is ab-
Treg-specific transcription factor Foxp3, which rogated (43). Although homodimerization of

is required for the induction and maintenance Foxp3 is not required for its inhibitory effect
of induced Treg cells (iTreg) in the peripheral on RORγt, whether or not Foxp3 needs a func-
immune compartment (64, 65). However, additional DNA-binding motif to inhibit RORγt is
tion of IL-6 to TGF-β inhibits the generation still unclear (43, 66). Foxp3 may also have to
of Tregs and induces Th17 cells. On the ba- bind both RORγt and additional transcription
sis of these data, we first put forward the idea factors such as Runx1, which also cooperates
that there is a reciprocal relationship between with RORγt, to fully inhibit the Th17 tran-
Tregs and Th17 cells and that IL-6 plays a piv- scriptional program (68).
otal role in dictating whether the immune re- The reciprocal relationship between Tregs
sponse is dominated by proinflammatory Th17 and Th17 cells is further supported by the re-
cells or protective Tregs (3). We propose that sults obtained in IL-6 KO mice, which show a
the unactivated immune system at a steady state severe defect in the generation of Th17 cells
(in the absence of inflammatory stimuli) pro- and increased numbers of Tregs in the periph-
duces TGF-β, which induces the generation eral repertoire (3, 5). Observations from other
of iTregs, which together with nTregs keep groups have further strengthened the idea of
activated/effector memory cells in check. IL- a reciprocal relationship between Tregs and
6, induced during an acute-phase response, in- Th17 cells (69, 70): IL-2, which is a growth fac-
hibits the function of nTregs and prevents the tor for Tregs, inhibits the generation of Th17
generation of iTregs, but instead induces Th17 cells and promotes the generation of Tregs (69).
cells. Thus, IL-6 plays a pivotal role in dictat- Subsequently, Il2−/− and Stat5−/− mice exhibit
ing the balance between the generation of Tregs reduced numbers of Tregs, and Il2−/− mice have
and Th17 cells. an increased frequency of Th17 cells in the
The mechanism by which IL-6 and IL-21 peripheral repertoire (69). Moreover, Il2−/− ,
act as switch factors relies on the control of Il2rα−/− , Il2rβ−/− , and Stat5−/− mice develop
the Foxp3/RORγt balance (43). In line with multi-organ inflammatory diseases that can be
this concept, conditional deletion of Foxp3 prevented by the transfer of Tregs (71–74),
in adult mice results in an increase in both suggesting that IL-2 receptor signaling pro-
RORγt and IL-17 expression (33). It is clear motes the generation of Tregs but inhibits Th17
now that TGF-β is required for the expres- cells in the peripheral immune compartment
sion of both Foxp3 and RORγt, although the in vivo.
signaling cascades downstream of the TGF-β Additional evidence for a reciprocal devel-
receptor might be different for the induction opmental relationship between Foxp3+ Tregs
of Foxp3 versus RORγt. For example, whereas and Th17 cells comes from studying the ef-
Smad4 appears to be essential for the induc- fects of retinoic acid, a vitamin A metabolite, on
494 Korn et al.

T cell differentiation. Retinoic acid could drive dependent system to control the generation
the generation of Tregs while abrogating the of Th17 versus iTregs in vitro and in vivo.
differentiation of Th17 cells, but not of Th1 A nonmetabolizable ligand of AHR, 2,3,7,8-
cells (70). CD103+ lamina propria DCs but not tetrachlorodibenzo-p-dioxin, induced the ex-
splenic DCs appear to be a relevant source of pression of Foxp3, resulting in the generation of
retinoic acid in vivo and, together with TGF- functional Tregs, whereas 6-formylindolo[3,2-
β, are efficient in inducing Foxp3+ Tregs de b]carbazole, another ligand of AHR, promoted
novo in vitro (75, 76). At the steady state, the the expression of Th17 cells (80, 82). En-
frequency of Foxp3+ Tregs in the lamina pro- dogenous ligands of the AHR exist; however,
pria of the gut is three times as high as in the their relevance in skewing the immune re-
secondary lymphoid tissue (77), suggesting that sponse toward Th17 cells or Tregs is not
the repertoire of antigen-specific Tregs in the known.
gut is induced and expanded by the local en- The question of whether reprogramming
vironment and driven in part by retinoic acid of either precommitted iTregs or Th17 cells
produced by CD103+ DCs. Retinoic acid is be- is possible was recently addressed in a study
lieved to act directly on naive T cells, enhanc- from Chen Dong’s laboratory (66). iTregs could
ing TGF-β signaling while inhibiting IL-6 sig- be reprogrammed to the Th17 phenotype in
naling. Mechanistically, retinoic acid enhances the presence of TGF-β plus IL-6 up to five
the TGF-β-driven phosphorylation of Smad3 days after differentiation (66). Foxp3 is down-
but reduces the TGF-β-induced upregulation regulated upon restimulation in the presence
of the IL-6Rα subunit on T cells. In the pres- of TGF-β plus IL-6; however, in the pres-
ence of both TGF-β and IL-6, retinoic acid ence of retinoic acid, IL-6 was unable to in-
suppresses the upregulation of IRF4 and IL- duce IL-17 from Foxp3+ T cells. Even natu-
23R, resulting in decreased generation of Th17 rally occurring Tregs begin to express IL-17
cells (78). It is clear that retinoic acid cannot under inflammatory conditions such as, for ex-
induce Tregs on its own, but rather needs to ample, in the target tissue of an autoimmune
cooperate with TGF-β to mediate its effects. reaction. We have observed that Foxp3+ T
Although the binding of retinoic acid by its nu- cells begin to express IL-17 in the CNS at
clear receptor RARα increases Foxp3 promoter the peak of disease during EAE (66; T. Korn
activity (79), the relevant mechanism of retinoic and V.K. Kuchroo, unpublished observation).
acid in modulating the balance between Treg IL-6 may be the most crucial factor in medi-
and Th17 cell development in vivo is not en- ating this conversion of Foxp3+ T cells into
tirely clear. The data of others and our own Th17 cells in vitro and in vivo (66; T. Korn and
group suggest that in an inflammatory setting, V.K. Kuchroo, unpublished observation). The
retinoic acid inhibits the generation of Th17 reexpression of the Th17 program in Foxp3+
cells rather than enhancing de novo generation T cells appears to be a two-step process that
of Tregs (70, 78). Collectively, these findings in- includes downregulation of Foxp3 and release
dicate that a common metabolite like retinoic of RORγt and RORα from Foxp3-mediated
acid can regulate the balance between proin- inhibition.
flammatory Th17 cells and anti-inflammatory
Tregs.
Moreover, in microarray screenings that ROLE OF IL-23
were undertaken to detect genes specifically IL-23, a member of the IL-12 family of cy-
upregulated in the Th17 or iTreg lineages, tokines, was first described in 2000 as a het-
the aryl hydrocarbon receptor (AHR) was de- erodimer composed of a p19 subunit and the
tected to be highly expressed in both the Th17 p40 subunit shared with IL-12 (17). The recep-
(80) and Treg signatures (81). In functional tor for IL-23 was described as being expressed
studies, AHR was identified to be a ligand- on activated/memory T cell populations (83). A

first clue concerning the role of IL-23 in shap- the loss of IL-23 but not IL-12 is associated
ing the T cell immune response came from the with a decrease in gut inflammation induced by
analysis of IL-23p19-deficient mice. In 2003, anti-CD40 antibody-activated cells of the in-
Cua et al. (8) discovered that p19-deficient nate immune system (87). IL-23 appears to in-
mice, in contrast to p35-deficient mice, were duce IL-17, IL-1, TNF, and IL-6 from cells of
resistant to the development of EAE and had the innate immune system (87, 88). Whether
very few cells capable of secreting IL-17 in the IL-23-mediated gut inflammation is entirely
CNS (8, 9). A stronger connection between IL- dependent on IL-17 produced by cells of the
23 and Th17 cells was established when inves- innate immune system has not been addressed.
tigators showed that IL-23 promotes the pro- Consistent with the importance of IL-23 in pre-
duction of IL-17 by activated T cells (84) and clinical models of inflammatory bowel disease
that IL-23-expanded T cells are able to trans- (87, 89–91), a genome-wide screen revealed
fer EAE and CIA (9, 85). IL-23R is clearly not that a particular coding variant of the IL23R
expressed on naive T cells, and after the identifi- gene (rs11209026, c.1142G>A, p.R381Q) con-
cation of the factors (IL-6, IL-21, and TGF-β) ferred strong protection from Crohn’s disease,
required for the differentiation of Th17 cells, whereas several variants in the noncoding re-
it became clear that IL-23 was not involved in gion of this gene were associated with in-
the initial differentiation of Th17 cells. Yet IL- creased susceptibility to Crohn’s disease (92).
23 appears to be essential for the full and sus- Similarly, other genome-wide association stud-
tained differentiation of Th17 cells given that ies (93, 94) revealed associations of IL23R gene
IL-23p19-deficient mice have limited numbers SNPs [R381Q: rs11209026 (same as in Crohn’s
of Th17 cells and that prolonged culture of disease) and L310P: rs7530511] with psoriasis,
Th17 cells in vitro requires the addition of IL- further strengthening the idea that IL-23R may
23. Similarly to IL-12 for Th1 cells, IL-23 could be involved in inducing human autoimmune
serve to expand and stabilize Th17 responses. diseases.
Alternatively, IL-23 may induce proinflam-
matory effector cytokines and suppress anti-
inflammatory cytokines like IL-10 in Th17 cells SKEWING OF Th17 RESPONSES
(86). But the precise function of IL-23 for Th17 BY MICROBIAL AGENTS
cells remains elusive, in part because the tim- Although IL-23 is not the differentiation fac-
ing and consistency of IL-23R expression on tor of Th17 cells, productive and sustained
T cells have been difficult to investigate. Initial Th17 responses only develop in the presence
studies proposed that IL-23R could be induced of IL-23, as revealed by studies with Il23p19−/−
by TGF-β (4). More recently, IL-6 and IL-21 and Il23r−/− mice. Indeed, after initial induc-
were shown to induce IL-23R in a STAT3- tion of Th17 cells, the availability of IL-23
dependent manner (7). But IL-23R appears apparently becomes the limiting factor that
also to be dependent on RORγt, as RORγt- determines whether the Th17 response is sus-
deficient mice have reduced expression of IL- tained during an immune and inflammatory re-
23R (6). Thus, combined signals of RORγt and sponse (32). Given that IL-23 is predominantly
STAT3, induced by IL-6/IL-21 together with produced by cells of the innate immune sys-
low amounts of TGF-β, might be required to tem, including DCs and macrophages in the
promote IL-23R expression and confer IL-23 gut, the signals that induce the production of
responsiveness. this cytokine might be critical in determining
In addition to its role for Th17 cells, IL- whether the T cell response is dominated by
23 also has an important role in the regu- Th17 cells. When mice were immunized with
lation of the innate immune response. The myelin antigen together with zymosan, a fungal
development of gut inflammation in T and B cell wall constituent, as an adjuvant that engages
cell–deficient mice depends on IL-23 in that Toll-like receptor 2 (TLR2) and DC-associated
496 Korn et al.

C-type lectin-1 (dectin-1) on DCs (95), IL-23 acid (polyI:C) might induce DCs to produce
was induced and Th17 cells were preferentially both IL-12p70 and IL-27 (99). IL-27 produced
generated in vitro and in vivo. This finding is by DCs has direct and STAT1-dependent
consistent with studies on human Th17 cells inhibitory effects on the differentiation of
in which memory T cells reactive against fun- Th17 cells (see below). IL-12 promotes Th1
gal cell wall products were mainly identified in cells whose IFN-γ production inhibits the
the CCR6+ CCR4+ Th17 subset (96). Further- generation of Th17 cells as well. Thus, TLR3
more, a genetic defect in the induction of IL-23 stimulation by polyI:C is likely to dampen
and IL-17 may result in fulminant and persis- Th17 responses. Accordingly, EAE is atten-
tent fungal infections in humans (97), which is uated by administration of polyI:C, although
also a feature of the autosomal dominant hy- this is primarily attributed to the fact that
per IgE syndrome owing to STAT3 mutations polyI:C is also able to induce type I interferons
and subsequent loss of Th17 cells (98), further and especially IFN-β (103). The induction of
supporting the role of the IL-23/IL-17 path- IFN-β by polyI:C is TLR3 independent.
way in clearing fungal infections. Thus, IL-23 TLRs target NF-κB but also IRFs that func-
is an important link between innate immune tion as transcription factors and—in certain
cells and adaptive Th17 responses. However, combinations—are able to transactivate p19,
the exact role of IL-23 in vivo still awaits fur- p28, p35, p40, and Epstein-Barr virus–induced
ther elucidation. gene 3 (EBI3) product. For example, c-Rel and
Upon stimulation with various microbial IRF5 induce the transcription of p19, p35, and
agents (pathogen-associated molecular pat- p40 and thus both IL-12p70 and IL-23, whereas
terns), which activate specific TLRs or dectin IRF1, IRF3, and IRF7 exclusively induce p35
receptors, DCs secrete IL-12p70, IL-23, or and p28 but not p19 and thus would induce
IL-27. When one of these cytokine signals IL-12 and IL-27 and not IL-23 (for review,
becomes dominant, it determines the type see 99).
of immunity that develops, i.e., whether the TLR signals can be modified by signals
immune response is skewed toward Th1 or from seven-transmembrane domain G protein–
Th17 cells. Much effort has focused on iden- coupled receptors. This is relevant because
tifying differential stimulation conditions and prostaglandin E2 (PGE2), by triggering the E
signaling pathways that lead to the secretion of prostanoid receptors EPR2 and EPR4 on DCs,
one or the other member of the IL-12 family of can shift the balance between IL-12 and IL-23
cytokines by DCs (for review, see 99). Whereas secretion toward IL-23 (104, 105).
TLR4 stimulation by LPS induces p19, p35, C-type lectins, unrelated to TLRs, are
and p40—thus producing both functional also pattern-recognition receptors expressed on
IL-12p70 and IL-23—stimulation of TLR2 DCs. Ligation of these receptors might bias
by peptidoglycan induces large amounts of DCs to produce IL-23. Indeed, zymosan and
IL-23 but not p35 (100). Interestingly, TLR2- curdlan, which are dectin agonists, induce se-
stimulation by Pam3 CysSerLys4 does not cretion of IL-23 and have been used as adju-
result in high levels of IL-23 (101). The reason vants to skew the T cell response toward Th17
for this is unclear. However, peptidoglycan also (32, 106). Moreover, the two forms of Candida
conveys signals through nucleotide-binding albicans—the yeast form and tissue-infiltrating
domain leucine-rich repeat–containing family hyphae form—appear to trigger distinct innate
proteins (NLR proteins), which enhance NF- immune responses. Whereas the yeast form in-
κB activation. Indeed, when DCs lack the NLR duces IL-12p70 by engaging TLR2, TLR4, and
protein NOD2, they are impaired in their dectin-1, the hyphae form of C. albicans induces
capacity to secrete IL-23 (102). Stimulation of IL-23 by activating dectin-2 and TLR2, but not
endosomal TLR3 by polyinosinic-polycytidylic TLR4 (96).

EFFECTOR FUNCTIONS OF Th17 human diseases as well. However, proof of a

CELLS IN HEALTH AND DISEASE pathogenic role for human Th17 cells is not
yet available. Nevertheless, good circumstan-
The concept that Th17 cells are a unique
tial evidence suggests that Th17 cells are im-
subset of effector T helper cells was first
portant in human psoriasis (114), rheumatoid
developed in organ-specific autoimmunity,
arthritis (115), multiple sclerosis (116), inflam-
where autoantigen-specific Th17 cells induce
matory bowel disease (92), asthma (117, 118),
severe autoimmune tissue inflammation. How-
and some bacterial and fungal infections.
ever, an early study on in vitro skewing of CD4+
In psoriasis, T cells extracted from psori-
T cells with microbial products showed that
atic skin lesions showed predominantly a Th17
lysate from Borrelia burgdorferi was able to in-
phenotype (119), which is in line with the ob-
duce massive amounts of IL-17 in T cell differ-
servation that CCL20/CCR6 signaling is an
entiation cultures (107). It is certainly not the
important pathway for chemoattraction of in-
primordial function of Th17 cells to induce au-

flammatory cells to epithelial tissues. More-

toimmunity, but the Th17 lineage constitutes
over, a phase II therapeutic trial with a mon-
a branch of the adaptive immune system that
oclonal antibody targeting p40 was extremely
has a function in the clearance of specific types
efficient in reducing affected psoriatic skin area
of pathogens that require a massive inflam-
(114). However, because this antibody neutral-
matory response and are not adequately dealt
izes both IL-12 and IL-23, the clinical effects
with by Th1 or Th2 immunity. Pathogens as
cannot be uniquely attributed to the IL-23/IL-
diverse as the Gram-positive Propionibacterium
17 axis, although studies from psoriasis-like skin
acnes; the Gram-negative Citrobacter rodentium,
disease in mice suggest that IL-23 and IL-22
Klebsiella pneumoniae, Bacteroides spp., and Borre-
are more important in lesion formation than
lia spp.; the acid-fast Mycobacterium tuberculosis;
IL-12/IFN-γ.
and fungi-like Pneumocystis carinii and Candida
Similarly, in rheumatoid arthritis patients,
albicans can all trigger a strong Th17 response
in a two-year prospective study, the cytokine
(4, 107–112).
expression of TNF, IL-1, and IL-17 was pre-
No specific surface marker has been iden-
dictive of joint destruction, whereas IFN-γ was
tified for Th17 cells, although expression
protective (115). Furthermore, direct effector
of RANKL and a certain combination of
functions of Th17 cells in rheumatoid arthritis
chemokine receptors has been associated with
have been demonstrated in that RANKL ex-
Th17 cells. In humans, coexpression of CCR4
pression on the surface of Th17 cells induces
and CCR6 (96) or expression of CCR2 in the
osteoclastogenesis (120–122), promoting carti-
absence of CCR5 (113) appears to define Th17
lage and bone destruction/resorption indepen-
cells in the memory cell compartment of pe-
dently of TNF and IL-1 (123, 124). Chon-
ripheral blood mononuclear cells (96). Interest-
drocytes and osteoblasts respond vigorously to
ingly, IL-17-producing memory CD4+ T cells
IL-17 by upregulating a plethora of proinflam-
contain a large fraction of cells reactive against
matory cytokines, chemokines, and proteases
fungal antigens, suggesting that Th17 cells may
(see below), and TNF, IL-1, and IL-6 induced
be preferentially induced in response to fungal
by IL-17 might even feed back on the genera-
infections and may play an important role in or-
tion and expansion of further Th17 cells in this
chestrating host defense against certain fungi,
specific microenvironment of the joint.
as discussed above (96).
In multiple sclerosis, the role of Th17 cells
On the basis of experimental animal stud-
has been more difficult to explore. IL-17 and
ies in infectious diseases, autoimmune condi-
IL-6 are among the most highly expressed
tions, transplantation reactions, allergy, and tu-
genes in multiple sclerosis lesions (125), and el-
mor, investigators have implicated Th17 cells
evated levels of IL-17 have been reported in
and Th17-associated cytokines in a variety of
498 Korn et al.

the serum and cerebrospinal fluid of multiple On the basis of the comparison of IL-17A ver-
sclerosis patients (116). In a correlative study, sus IL-17F KO mice in various disease condi-
IL-17 and CXCL8 (IL-8), which is a target of tions, investigators have suggested overlapping
IL-17 and a strong neutrophil-chemoattractant but differential functions of IL-17A versus IL-
(see below), were more elevated in opticospinal 17F (131). For example, Dong and colleagues
forms of multiple sclerosis than in conventional (131) suggested that IL-17A but not IL-17F
multiple sclerosis patients (126). Interestingly, was required to induce EAE, whereas IL-17F
the level of IL-17 in the cerebrospinal fluid of but not IL-17A was required to induce airway
opticospinal multiple sclerosis patients had a neutrophilia upon allergen stimulation and se-
significant correlation with the extent of spinal vere immunopathology in the dextran sulfate
lesions as measured by MRI (126). An in vitro sodium (DSS)-induced colitis model.
study suggested that human Th17 cells might Moreover, although the differentiation con-
be well equipped to breach the blood-brain ditions necessary for Th17 cells to yield max-
barrier and infiltrate the CNS parenchyma imum expression of IL-17A and IL-17F are
(127). In monocyte-derived DCs from periph- similar, there are differences in the conditions
eral blood of multiple sclerosis patients, the ex- for the maximum upregulation of the other cy-
pression of IL-23p19 was increased, and this tokines associated with the Th17 phenotype, as
correlated with an enhanced capacity of these has been reported for IL-22 (132) (see above).
DCs to induce IL-17 production in T cells This suggests that Th17 cells might vary in their
(128). Together with the recent studies in EAE, effector functions depending on the combina-
this suggests an important role for the IL- tion of effector cytokines produced by Th17
23/IL-17 axis in the pathogenesis of multiple cells and the corresponding receptor distribu-
sclerosis as well. tion in the target tissue.
Mechanistically, the effector functions of
Th17 cells have been partly characterized
(Table 1). The cytokines produced by Th17 IL-17 AND IL-17R
cells allow Th17 cells to communicate with a IL-17 is the founding member of the IL-17
wide variety of immune and nonimmune cells. family of cytokines, which includes IL-17A
Whereas IL-21 (which is produced in large (also called IL-17), IL-17B, IL-17C, IL-17D,
amounts by Th17 cells) acts on other immune IL-17E (also called IL-25), and IL-17F (169,
cells such as B cells and feeds back to further am- 170). IL-17E (or IL-25) is not produced by
plify Th17 responses, other cytokines produced Th17 cells, but it is produced by Th2 cells
by Th17 cells, including IL-17, IL-17F, and IL- (171). IL-25 induces the expression of Th2-
22, have broad effects on many cell types and type cytokines and chemokines such as CCL5
induce the production of proinflammatory cy- (RANTES) and CCL11 (Eotaxin) and might be
tokines and chemokines to attract neutrophils involved in Th2-type allergic responses (171).
to the site of inflammation and antimicrobial Whereas other members of the IL-17 family
peptides to strengthen host defense directly map to different chromosomes, Il17a and Il17f
(Table 1). on mouse chromosome 1 are syntenic to the
Th17 cells were named after their produc- human genes on chromosome 6.
tion of the signature cytokine IL-17A. How- Besides being produced by Th17 cells, both
ever, they also produce IL-17F, IL-21, IL-22, IL-17A and IL-17F are also produced by a va-
GM-CSF, and potentially TNF and IL-6. The riety of cell types, including γδ T cells, NKT
conditions to induce IL-17A have been well de- cells, NK cells, neutrophils, and eosinophils
fined, and IL-17A and IL-17F are largely coex- (117, 172–176). Thus, IL-17 and IL-17F are
pressed in CD4+ T cells (129, 130), yet there effector cytokines that are produced by cells
may be conditions in which subsets of Th17 of both the innate and the adaptive immune
cells may only produce IL-17A or IL-17F (131). systems, suggesting a bridging function of this

Table 1 Functions of Th17-associated effector cytokines

Overall
Disease/condition Cytokine evaluation Experimental approaches and mechanisms References
EAE/multiple sclerosis IL-23 pathogenic IL-23p19 and IL-23R KO mice are resistant to EAE. 8
IL-23R is expressed in macrophages infiltrating the CNS M. Oukka,
and macrophages expressing IL-23R respond to IL-23 by unpublished
expressing IL-17 and IL-22. observation
IL-17 pathogenic IL-17A KO mice (IL-17F not reduced) have milder disease. 133, 134
Independently generated strain of IL-17A KO mice 131
(reduced levels of IL-17F) exhibit significantly reduced
EAE.
IL-17F KO mice (normal levels of IL-17A). EAE 131
marginally reduced in IL-17F KO mice. However, in
airway hypersensitivity, neutrophil recruitment is severely

reduced in IL-17F KO mice, whereas eosinophilic

infiltration is increased.
Anti-IL-17A antibody treatment attenuates EAE but does 135
not abrogate the disease.
IL-17 is highly expressed in chronic multiple sclerosis 125
lesions.
IL-17 was found in T cells (CD4+ and CD8+ ) and 136
astrocytes of multiple sclerosis lesions.
Human Th17 cells are required to breach the blood-brain 127
barrier, which is due to production of IL-17 and IL-22.
IL-22 no effect IL-22 KO mice are not protected from EAE. 137
IL-21 ? IL-21R KO have decreased Th17 frequencies in the 5, 53, 54
memory T cell compartment but are not resistant to EAE
after immunization with autoantigen in CFA.
Inflammatory skin IL-23 pathogenic IL-23 is overproduced by keratinocytes and DCs in 132, 138
disease in mice and psoriatic skin lesions, and injection of IL-23 induces
psoriasis in humans hyperkeratosis.
Variants of IL-23R and IL-12B confer resistance to 93, 139, 140
psoriasis. Genetic data on IL-23 and IL-12 assign
importance to both IL-12 and IL-23.
IL-23R data clearly identify IL-23 as major pathogenic 141
factor in psoriasis.
Efficiency of ustekinumab (human anti-IL-12/23 142
monoclonal antibody) in psoriasis in a phase III clinical
trial.
IL-17 pathogenic Higher frequencies of Th17 cells, but not Th1 cells in 143
psoriatic lesions: IL-17A+ , IL-17A/TNF+ ,
IL-17A/IFN-γ + .
Anti-TNF therapy in psoriasis works by decreasing Th17 144
cells.
IL-15 triggers IL-17 from human T cell blasts and IL-15 145, 146
gene variants (SNP polymorphisms) are associated with
psoriasis.
IL-22 pathogenic IL-22 promotes proliferation of keratinocytes. 132, 147, 148
IL-22 is required for skin inflammation in a model for 149
psoriasis.
(Continued )
500 Korn et al.

Table 1 (Continued )
Overall
IL-21 not Region of human chromosome 4 harboring IL2 and IL21 94
evaluated genes was identified as a potential disease susceptibility
locus in genome-wide association study.
Inflammatory bowel IL-23 pathogenic IL-23p19 KO mice have reduced T cell–dependent 89, 91
disease colitis.
IL-23 is essential for driving T cell–dependent colitis in 150
IL-10 KO mice.
IL-23p19 but not IL-12p35 is required for mediating gut 87, 89
inflammation in a T cell–independent manner, i.e., in Rag
KO mice induced with either Helicobacter hepaticus or
anti-CD40 treatment.
T cell–independent sources of IL-17 are neutrophils and 89, 151

monocytes/macrophages.
Anti-IL-23p19 cures IBD in mice, and anti-p40 treatment 152, 153
in humans is beneficial in Crohn’s disease and is associated
with decreased IL-12 and IL-23.
IL-23R SNP polymorphisms protect from Crohn’s disease. 92
IL-17 ? Th17 cells are more potent in transferring IBD than Th1 152
cells.
IL-17 is produced in healthy gut. 154
Blockade of IL-17A in colitis of IL-10 KO mice is 150
inefficient in reducing disease unless IL-6 is also
neutralized.
Anti-IL-17A monoclonal antibody treatment aggravates 155
DSS-induced colitis.
IL-17A protective in DSS-induced colitis (IL-17A KO 131
mice have increased disease with higher levels of CCL2,
CCL5, and CCL7 in the colon tissue).
IL-17F increases DSS-induced colitis (IL-17F KO mice
are relatively protected).
IL-22 protective IL-22 can be protective in preserving the epithelial barrier 154
function in C. rodentium infection.
IL-21 ?
Experimental arthritis/ IL-23 pathogenic IL-23p19 KO mice are protected from CIA. 85
rheumatoid arthritis
PGE2 promotes IL-23 and enhances IL-17 levels in the 104
joints of CIA animals.
IL-17 pathogenic IL-17 KO mice have reduced CIA. 156
Vaccination against IL-17A reduces arthritis. 157
TLR-4 KO IL-1Ra KO mice are protected from arthritis, 158–160
whereas TLR-2 KO IL-1Ra KO are highly susceptible
owing to lack of Tregs.
Expansion of autoreactive Th17 cells drives RA by
autoamplification loops.
Th17 cells through secretion of IL-17A act on osteoblastic 122
cells inducing RANKL. Interaction between RANK on
osteoclast precursors and RANKL results in the
differentiation of osteoclasts and bone resorption.
(Continued )

Table 1 (Continued )
Overall
Th17 cells expressing CCR6 migrate to the joints and produce 161
CCL20 to attract other CCR6-expressing cells.
Chemoattraction of B cells by Th17 cells: synovial fluid Th17 162
but not Th1 cells express CXCL13.
IL-22 ? IL-22R expressed on synovial fibroblasts of rheumatoid arthritis 163
patients. IL-22 induces proliferation of synovial fibroblasts.
IL-21 pathogenic Blockade of IL-21 signaling by administration of IL-21R-Fc 164
fusion protein attenuated CIA.
Host defense IL-23 protective IL-23p19 KO and IL-17R KO are greatly susceptible to 165
K. pneumoniae.
Citrobacter rodentium: Induction of Th17 cells in the absence of 4

IL-23p19 in the gut mucosa, but no protective immunity.

IL-17 protective IL-17A KO are greatly susceptible to K. pneumoniae: IL-17A 134
promotes neutrophil recruitment in infection with
K. pneumoniae.
Bordetella pertussis-LPS induces IL-23 in DCs in a 166
TLR4-dependent manner resulting in Th17 expansion. IL-17
enhances bactericidal properties of macrophages.
CD4+ T cell–derived IL-17 and IL-17F induce lung neutrophil 167
infiltration and contribute to pathogen clearance in a murine
model of acute respiratory tract infection with Mycoplasma
pneumoniae.
IL-17-driven chemokine expression is required to attract 110
protective IFN-γ-producing Th1 cells in Mycobacterium
tuberculosis infection.
IL-17RA KO mice are more susceptible to Candida albicans 112
infection than wild-type mice, and administration of IL-17A to
wild-type mice protects from lethal doses of C. albicans.
Th17 cells in memory compartment of humans have high 96
frequency of Candida-specific TCRs.
IL-22 protective IL-22 is essential for mucosal immunity against pathogens. 134
Together with IL-17 or IL-17F, IL-22 synergistically induces 130
antimicrobial peptides in keratinocytes.
IL-21 ? Although not required to restrain the pathogen burden in 168
Schistosoma mansoni infection, IL-21 promotes Th2-driven
immunopathology. IL-21R KO have less Th2-associated
cytokines (IL-4 and IL-13) in the lung draining lymph nodes
and less Th2-driven granuloma formation in the liver despite
equal parasite loads.
type of immunity between innate and adap- pression of cytokines (TNF, IL-1β, IL-6, GM-
tive immune responses. The conditions for the CSF, G-CSF), chemokines (CXCL1, CXCL8,
induction of IL-17A and IL-17F in CD4+ T CXCL10), and metalloproteinases (18, 177–
cells are similar. Both IL-17A and IL-17F have 184). Moreover, human Th17 cells produce
proinflammatory properties (39) and act on a CCL20 themselves (27). CCL20 is a ligand
broad range of cell types to induce the ex- for CCR6 and has antimicrobial as well as
502 Korn et al.

chemoattractive activity (185). Notably, human alternatively spliced mRNAs appear to exist
Th17 cells express CCR6 (96). IL-17A and IL- for all IL-17R family members, and IL-17RB
17F are also key cytokines for the recruitment, and IL-17RC are predicted to have soluble iso-
activation, and migration of neutrophils (169, forms with conserved ligand-binding capacity
186). acting as decoys. As mentioned, some mem-
Interestingly, IL-17 was reported to be a fac- bers of the IL-17R family can form dimers or
tor that contributes to the formation of ger- oligomers with other chains from the same fam-
minal centers (GC) of lymph follicles retaining ily. It is unclear whether IL-17R family mem-
B cells within GCs and enhancing somatic hy- bers can also associate with chains from differ-
permutation, presumably through modulation ent cytokine receptor families. Although IL-17
of chemokine activity (187). In this study, the seems to activate mitogen-activated protein ki-
source of IL-17 was identified as Th17 cells nase (MAPK) pathways and NF-κB via TRAF-
but not T follicular helper cells. In the current 6 (194, 195) and interact with the membrane
understanding, T follicular helper cells express proximal adapter Act1 (196, 197), the signaling
CXCR5 and thus respond to the lymph follicle– cascade downstream of the IL-17R complexes
associated chemokine CXCL13 and home to is not yet known.
and help establish the light zone of GCs, where IL-17RA is the cognate receptor for IL-17.
they give cognate help to B cells that have IL-17RA binds both IL-17A and IL-17F, al-
undergone immunoglobulin isotype switching though it binds to IL-17A with higher affin-
and somatic hypermutation in the GC dark ity (186). IL-17RA is highly expressed on
zone (188). Thus, T follicular helper cells in hematopoietic cells, but also—at lower levels—
the GC light zone induce further differentia- on osteoblasts, fibroblasts, endothelial cells, and
tion and selection of B cells. Both Th17 and epithelial cells. In humans IL-17RA can form
T follicular helper cells are a major source of a heterodimer with IL-17RC that binds hu-
IL-21, and therefore both may play an impor- man IL-17A and IL-17F (190). IL-17RC is the
tant role in setting up productive GC reactions cognate receptor for IL-17F (189). In contrast
(187). to IL-17RA, IL-17RC is expressed only at low
The IL-17 receptors constitute a distinct levels on hematopoietic cells, but is highly ex-
family of cytokine receptors (186). The IL-17R pressed on nonhematopoietic cells. Whereas
family includes IL-17RA, IL-17RB, IL-17RC, human IL-17RC also binds IL-17A, mouse IL-
IL-17RD, and IL-17RE. Whereas IL-17RA 17RC appears to be specific for IL-17F and does
and IL-17RC are the receptors for IL-17A and not bind mouse IL-17A (189).
IL-17F (177, 189, 190), IL-17RB (also called The best functional data exist for IL-17RA,
IL-17RH1 and EVI27) is the receptor for IL- and most experimental paradigms deal with
17E (IL-25) (191) but also binds IL-17B with models of infectious diseases in which IL-17R
low affinity (192). IL-17RB signaling promotes signaling is protective by initiating granu-
Th2-type immunity. However, in a recent study lopoiesis and orchestrating neutrophil traffick-
IL-25 needed to engage both IL-17RB and IL- ing. IL-17RA KO mice suffer from severe defi-
17RA to induce IL-5 and IL-13, suggesting that ciencies in host defense against Klebsiella (108)
the functional IL-25R complex might be a het- and Candida (112). Porphyromonas gingivalis–
eromeric receptor consisting of IL-17RA and driven bone destruction is increased in IL-
IL-17RB subunits in mouse and human (193). 17RA KO mice (198). Although the adaptive
Thus, IL-17RA not only conveys proinflamma- immune response against Toxoplasma gondii ap-
tory IL-17 effects, but also contributes in IL- pears to be intact in IL-17RA KO mice, the
25 signaling. The ligands for IL-17RD and IL- animals experience an increased mortality ow-
17RE are not known. IL-17R family members ing to deficiency of neutrophil recruitment to
have one transmembrane domain and a large the site of infection (199). The myelotoxicity
intracellular C terminus. Except for IL-17RA, of γ irradiation is increased in IL-17RA KO

mice owing to impaired hematopoietic recov- IL-22 on liver cells can be abrogated by overex-
ery (200). Thus, IL-17 induces a broad tissue pression of SOCS3 (210). Importantly, a soluble
response leading to neutrophil trafficking to the IL-22-binding protein (IL-22BP) has been dis-
site of inflammation. Whereas the clearance of covered that lacks transmembrane and signal
some pathogens essentially depends on this re- transduction domains (211). IL-22BP is pro-
sponse, other pathogens such as certain viruses duced by LPS-stimulated monocytes and neu-
(201), bacteria such as Pseudomonas aeruginosa tralizes IL-22-driven STAT3 activation (212).
(202), and fungi such as Aspergillus fumigatus Part of the complex effects of IL-22 may be due
(203) induce the production of IL-17, but can to the existence of this endogenous antagonist
be controlled and finally cleared irrespective of IL-22 that appears to be upregulated under
of a strong neutrophil infiltration. In this sce- inflammatory conditions.
nario, IL-17-driven inflammation is no longer IL-22 induces antimicrobial agents in ker-
protective but carries the risk of severe im- atinocytes (130) and is essential in the im-
munopathology and autoimmunity. mune barrier function of epithelia, as shown in

bronchial infection models with Klebsiella (134)
and gut infection with Citrobacter (154). Fur-
IL-22 AND IL-22R thermore, IL-22 induces keratosis in mouse
IL-22 is a cytokine of the IL-10 family of cy- models of psoriasis and plays a role in hu-
tokines. This family further comprises IL-19, man psoriasis as well (213). IL-22 may pro-
IL-20, IL-24, IL-26, IL-28, and IL-29. IL-22 mote the breach of the blood-brain barrier in T
was cloned from a murine T cell lymphoma cell–mediated CNS autoimmunity (127). The
line that had been stimulated with IL-9 (204). sources of IL-22 in these various disease con-
IL-22 is produced by terminally differentiated ditions are not always Th17 cells. Whereas
Th17 cells and appears to be produced by Th17 IL-22 is derived from non-T cell and non-B
cells in response to IL-23 (86). Thus, robust ex- cell sources in Citrobacter-induced gut inflam-
pression of IL-22 in Th17 cells requires the ex- mation and is indeed secreted by DCs (154),
pression and triggering of the IL-23R in those T cells are the most relevant source of IL-22
cells. Because high concentrations of TGF- in Klebsiella infection of the respiratory tract
β inhibit the expression of IL-23R (43), IL- (134). Similarly, Th17 cells are the main pro-
22 is also repressed by high concentrations of ducers of IL-22 in EAE. However, because
TGF-β. IL-22-deficient mice are not resistant to EAE
Like the IL-17R, the receptor for IL-22, (137), IL-22 on its own does not define the
which is a heterodimer of the specific IL-22R pathogenicity of Th17 cells. Rather, a combi-
and the IL-10R2 (205, 206), is widely expressed, natorial expression of effector cytokines likely
including in epithelial and endothelial cells contributes to the potential pathogenicity of
(207). However, in contrast to the IL-17R, the Th17 cells. IL-22 might not always be proin-
IL-22R is not expressed on immune cells, and flammatory and may even protect from im-
thus IL-22 is used by Th17 cells to commu- munopathology under certain circumstances.
nicate with tissues but not with other immune For example, IL-22 is protective in inflamma-
cells. Besides associating with IL-10R2, IL-22R tion of the liver (214), the gut (154, 215), and
can also associate with IL-20R2, and the het- the myocardium (216). In experimental con-
erodimeric IL-22R/IL-20R2 complex is a func- canavalin A–induced hepatitis in mice, Th17
tional receptor for IL-20 and IL-24 (208). Sig- cells are a vehicle for delivering IL-22 into the
nal transduction through the IL-22R activates site of inflammation to limit liver damage (214).
MAPK pathways (Erk, Jnk, p38) and STAT3, Moreover, IL-22 induces LPS-binding protein
and activation of STAT1 and STAT5 have also and thus could also prevent systemic inflam-
been described (205, 209). STAT3 activation is mation by neutralizing LPS in case of bacterial
functionally relevant given that in vivo effects of infection or intestinal bacterial transmigration
504 Korn et al.

in inflammatory bowel disease (217). Thus, IL- recent reports suggest (a) that IL-27 together
22 as an effector cytokine of Th17 cells ap- with TGF-β might be the differentiation fac-
pears to be complex and probably redundant tor for IL-10-producing T cells that have Tr1-
in some aspects. Collectively, the available data like properties and (b) that IL-27R-deficient
point to an important role for IL-22 in epithe- (Wsx1−/− ) mice had a defect in generating IL-
lial and endothelial barrier function. Interest- 10-producing Tr1 cells (222–224). Thus, IL-27
ingly, the dual effect of IL-22 in promoting might also be necessary to control exaggerated
inflammation and tissue repair might be deter- immunopathology indirectly by inducing Tr1
mined on several levels: first by various combi- cells.
nations of Th17-derived effector cytokines that
are co-produced together with IL-22, and sec-
ond by the downstream effector molecules of CONCLUDING REMARKS: THE
IL-22 that are specifically and differentially in- CONCEPT OF Th17 IMMUNITY
duced in various target tissues. Since the identification of Th17 cells, much
progress has been made in understanding their
development and in defining the type of immu-
REGULATION OF Th17 nity that is mediated by this subset of effector
IMMUNITY T helper cells. Specific pathogens trigger Th17
IL-27 is a member of the IL-12 family of cy- responses, and productive Th17 responses are
tokines and is produced by cells of the innate required to clear many pathogens, presumably
immune system. IL-27 consists of two subunits, because Th1 or Th2 responses are not protec-
p28 and the EBI3 product. The IL-27 receptor tive in these conditions. The molecular mech-
is a heterodimer that is composed of a specific anisms by which an adaptive immune response
IL-27R subunit (also called WSX-1) and the is skewed toward a Th17 response appear to
gp130 subunit that is shared with the IL-6 re- rely in part on the ability of specific pathogen-
ceptor family (83). IL-27 was initially described associated molecular patterns to trigger cells
as inducing T-bet and enhancing Th1 re- of the innate immune system to produce cy-
sponses (218), but IL-27 also has dominant anti- tokines, specifically IL-23, that favor the de-
inflammatory properties (219). Thus, analysis velopment of Th17 cells. IL-17 and Th17 re-
of IL-27R-deficient mice revealed increased sponses are so important in these conditions
inflammation in an infectious disease model that patients with a genetic defect in the IL-
and increased neuroinflammation in EAE (220, 23/IL-17 axis develop devastating fungal infec-
221). Lack of IL-27 signaling resulted in an in- tions that cannot be controlled even though
creased Th17 response that could account for productive Th1 or Th2 responses are gener-
enhanced tissue inflammation. The inhibition ated in these patients.
of Th17 responses by IL-27 depends on STAT1 Thus, like adaptive Th1 and Th2 responses,
signaling, but did not require T-bet, IFN-γR, the development of Th17 immunity requires
or IL-6 receptor signaling (220, 221). Thus, IL- cues from the innate immune system. However,
27 dampens Th17 responses independently of compared with the differentiation of Th1 and
cross-inhibition as a result of enhanced Th1 Th2 cells, the requirement of TGF-β for the
commitment of activated T cells. However, IL- differentiation of Th17 cells is one of the fun-
27 has even broader effects, as lack of IL-27 damental differences in the induction of this ef-
signaling not only results in enhanced Th17- fector T cell subset. It is very surprising that an
mediated immunopathology, but also in tissue immunosuppressive cytokine is required for the
inflammation mediated by Th1 cells. These re- induction of a T helper cell subset with highly
sults suggest that there is a more generalized proinflammatory properties. At the functional
defect in regulation of proinflammatory T cells, level, the requirement of TGF-β for the in-
which is dependent on IL-27. Indeed, three duction of both Foxp3+ Tregs and Th17 cells

might provide a system to efficiently balance cells. Although findings in preclinical models of
between tolerance and immunity: In the steady chronic inflammation and autoimmunity con-
state, TGF-β induces Foxp3 and Tregs, inhibits firm this hypothesis, many questions remain
inflammation, and maintains self-tolerance, but concerning the plasticity of developing Th17
once IL-6 is produced by innate immune cells cells. It remains to be determined how far Th17
in response to microbial triggers, Treg gener- cells and also Tregs can proceed in their devel-
ation is prevented, and the function of nTregs opmental pathway and still be able to be repro-
is suppressed while Th17 cells are induced to grammed to attain the other phenotype. An-
produce a strong proinflammatory response. At other field of considerable uncertainty relates to
the molecular level, the balance between Tregs the effector functions of Th17 cells. The effec-
and Th17 cells is maintained by the induction tor cytokines of Th17 cells may have differen-
of Foxp3 and RORγt and their association with tial and sometimes opposing effects in various
each other. target tissues. Nevertheless, accumulating data
The steps necessary for the terminal com- suggest that Th17-mediated immune responses
mitment of Th17 cells have been identified are very important in host defense but also in
based on the discoveries that IL-21 acts in promoting chronic inflammation and autoim-
an autoamplification loop and that IL-23 fur- munity. It is envisioned that the IL-23/IL-17
ther matures and expands precommitted Th17 axis will provide important new targets that al-
cells. We have proposed a three-step model: low us to dampen Th17-driven immunopathol-
(a) TGF-β plus IL-6 induces the differentiation ogy and promote the generation of Foxp3+
of Th17 cells, (b) IL-21 amplifies the frequency Tregs while at the same time sparing the protec-
of Th17 cells, and (c) IL-23 terminally differ- tive function of Th17 immunity in host defense
entiates and stabilizes the phenotype of Th17 and tissue repair.
SUMMARY POINTS
1. Besides Th1 and Th2 cells, Th17 cells constitute a third subset of effector T helper cells
with distinct effector functions. The differentiation factors (TGF-β plus IL-6 or IL-21)
and specific transcription factors (STAT3, IRF4, RORγt, and RORα) that define the
Th17 transcriptional program have been identified.
2. Th17 cells are reciprocally related to Foxp3+ Tregs given that TGF-β induces Foxp3
in naive T cells, whereas IL-6 suppresses the TGF-β-driven induction of Foxp3, and
TGF-β plus IL-6 together induce RORγt and the Th17 transcriptional program. At the
molecular level, the balance between Th17 cells and Foxp3+ Tregs is mediated by the
antagonistic interaction of the transcription factors Foxp3 and RORγt.
3. IL-21 is produced by Th17 cells themselves, and IL-21 together with TGF-β is able
to induce Th17 differentiation. Thus, IL-21 may be part of a positive feedback loop to
amplify the precursor frequency of Th17 cells.
4. IL-23 is not the differentiation factor of Th17 cells. However, IL-23 stabilizes differ-
entiating Th17 cells and leads to the further maturation of Th17 cells, for example by
inducing IL-22 in Th17 cells.
5. Th17 cells are important effector cells in host defense against certain pathogens such as
Candida albicans and specific extracellular bacteria. However, the broad receptor distri-
bution of IL-17 and IL-22 results in a massive tissue response upon activation of Th17
cells. This broad response to Th17-related effector cytokines might be the basis for the
prominent capability of Th17 cells to induce tissue inflammation and autoimmunity.
506 Korn et al.

FUTURE ISSUES
1. How are the signals of the immunosuppressive cytokine TGF-β and the signals induced
by IL-6 or IL-21 integrated to antagonize each other and result in the Th17 transcrip-
tional program?
2. Is there plasticity between committed Th17 cells and Tregs in vivo?
3. What effector cytokine or what combination of Th17-derived effector cytokines mediate
the effector functions of Th17 cells in various tissues?
4. Do Th17 cells have to cooperate with other T helper cell subsets to induce tissue inflam-
mation and autoimmunity?
5. How are Th17 cells regulated in vivo?
DISCLOSURE STATEMENT
The authors are not aware of any affiliations, memberships, funding, or financial holdings that
might be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENTS
This work was supported by grants from the National Multiple Sclerosis Society, the National
Institutes of Health, the Juvenile Diabetes Research Foundation Center for Immunological Toler-
ance at Harvard, and the Deutsche Forschungsgemeinschaft (KO 2964/2-1). V.K. Kuchroo is the
recipient of the Javits Neuroscience Investigator Award from the National Institutes of Health.
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cells. Nat. Immunol. 8:1372–79

AR371-FM ARI 16 February 2009 15:37
Annual Review of
Immunology
Contents Volume 27, 2009
Frontispiece
Marc Feldmann p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p x
Translating Molecular Insights in Autoimmunity into Effective
Therapy
Marc Feldmann p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p1
Structural Biology of Shared Cytokine Receptors
Xinquan Wang, Patrick Lupardus, Sherry L. LaPorte,
and K. Christopher Garcia p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 29
Immunity to Respiratory Viruses
Jacob E. Kohlmeier and David L. Woodland p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 61
Immune Therapy for Cancer
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Microglial Physiology: Unique Stimuli, Specialized Responses
Richard M. Ransohoff and V. Hugh Perry p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p119
The Liver as a Lymphoid Organ
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Immune and Inflammatory Mechanisms of Atherosclerosis
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Primary B Cell Immunodeficiencies: Comparisons and Contrasts
Mary Ellen Conley, A. Kerry Dobbs, Dana M. Farmer, Sebnem Kilic,
Kenneth Paris, Sofia Grigoriadou, Elaine Coustan-Smith, Vanessa Howard,
and Dario Campana p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p199
The Inflammasomes: Guardians of the Body
Fabio Martinon, Annick Mayor, and Jürg Tschopp p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p229
Human Marginal Zone B Cells
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v
AR371-FM ARI 16 February 2009 15:37
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Regulatory Lymphocytes and Intestinal Inflammation
Ana Izcue, Janine L. Coombes, and Fiona Powrie p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p313
The Ins and Outs of Leukocyte Integrin Signaling
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Recent Advances in the Genetics of Autoimmune Disease
Peter K. Gregersen and Lina M. Olsson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p363
Cell-Mediated Immune Responses in Tuberculosis

Andrea M. Cooper p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p393

Enhancing Immunity Through Autophagy
Christian Münz p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p423
Alternative Activation of Macrophages: An Immunologic Functional
Perspective
Fernando O. Martinez, Laura Helming, and Siamon Gordon p p p p p p p p p p p p p p p p p p p p p p p p451
IL-17 and Th17 Cells
Thomas Korn, Estelle Bettelli, Mohamed Oukka, and Vijay K. Kuchroo p p p p p p p p p p p p p p485
Immunological and Inflammatory Functions of the Interleukin-1
Family
Charles A. Dinarello p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p519
Regulatory T Cells in the Control of Host-Microorganism Interactions
Yasmine Belkaid and Kristin Tarbell p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p551
T Cell Activation
Jennifer E. Smith-Garvin, Gary A. Koretzky, and Martha S. Jordan p p p p p p p p p p p p p p p591
Horror Autoinflammaticus: The Molecular Pathophysiology of
Autoinflammatory Disease
Seth L. Masters, Anna Simon, Ivona Aksentijevich, and Daniel L. Kastner p p p p p p p p p621
Blood Monocytes: Development, Heterogeneity, and Relationship
with Dendritic Cells
Cedric Auffray, Michael H. Sieweke, and Frederic Geissmann p p p p p p p p p p p p p p p p p p p p p p p p669
Regulation and Function of NF-κB Transcription Factors in the
Immune System
Sivakumar Vallabhapurapu and Michael Karin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p693
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IL-17 and Th17 Cells

• Our comprehensive search

Annu. Rev. Immunol. 2009. 27:485–517 Key Words

INTRODUCTION human inﬂammatory conditions. In the past

Th2 cells. Th2 cells are key in organizing host

β in combination with other cytokines for the

486 Korn et al.

However, the concept that organ-speciﬁc au-

www.annualreviews.org • Th17 Cells 487

T naive Th17 Innate immune cell

488 Korn et al.

Th17 cells. ferentiation was performed in the presence of

www.annualreviews.org • Th17 Cells 489

of TGF-β by T cells resulted in more severe It remains to be determined whether other

Th2 responses, indicating that Treg-derived general, as well as by IL-2- or IL-12-stimulated

490 Korn et al.

ROLE OF IL-6 sion of IL-6Rα, TCR stimulation as well as

covered properties as a myeloma growth factor,

www.annualreviews.org • Th17 Cells 491

492 Korn et al.

subsequent differentiation of Th cell subsets Mice with conditional deﬁciency of STAT3

www.annualreviews.org • Th17 Cells 493

Treg-speciﬁc transcription factor Foxp3, which rogated (43). Although homodimerization of

494 Korn et al.

www.annualreviews.org • Th17 Cells 495

496 Korn et al.

www.annualreviews.org • Th17 Cells 497

EFFECTOR FUNCTIONS OF Th17 human diseases as well. However, proof of a

primordial function of Th17 cells to induce au-

ﬂammatory cells to epithelial tissues. More-

498 Korn et al.

www.annualreviews.org • Th17 Cells 499

Table 1 Functions of Th17-associated effector cytokines

airway hypersensitivity, neutrophil recruitment is severely

reduced in IL-17F KO mice, whereas eosinophilic

500 Korn et al.

T cell–independent sources of IL-17 are neutrophils and 89, 151

www.annualreviews.org • Th17 Cells 501

Citrobacter rodentium: Induction of Th17 cells in the absence of 4

IL-23p19 in the gut mucosa, but no protective immunity.

502 Korn et al.

www.annualreviews.org • Th17 Cells 503

munopathology and autoimmunity. mune barrier function of epithelia, as shown in

504 Korn et al.

www.annualreviews.org • Th17 Cells 505

506 Korn et al.

www.annualreviews.org • Th17 Cells 507

508 Korn et al.

www.annualreviews.org • Th17 Cells 509

510 Korn et al.

www.annualreviews.org • Th17 Cells 511

512 Korn et al.

www.annualreviews.org • Th17 Cells 513

514 Korn et al.

www.annualreviews.org • Th17 Cells 515

516 Korn et al.

lipopolysaccharide-binding protein in hepatocytes: a potential systemic role of IL-22 in Crohn’s dis-

www.annualreviews.org • Th17 Cells 517

Contents Volume 27, 2009

Cell-Mediated Immune Responses in Tuberculosis

Andrea M. Cooper p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p393

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