International Immunopharmacology 11 (2011) 319–322

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International Immunopharmacology
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i n t i m p

Th17 cells in inflammation

Akihiro Kimura b, Tadamitsu Kishimoto a,⁎
a
Laboratory of Immune Regulation, Osaka University Graduate School of Frontier Biosciences, Osaka, Japan
b
Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan

a r t i c l e i n f o a b s t r a c t

Article history: Naïve T cells are multipotential precursors that differentiate into various effector subsets, such as T helper type 1
Received 18 August 2010 (Th1) and Th2 cells, which are characterized by their distinct functions. The IL-17-producing T helper (Th17) cell
Accepted 1 October 2010 has been recently identified as a new subset of the T helper cell and a mediator of inflammation associated with
Available online 28 October 2010
various autoimmune diseases. Although several cytokines participate in Th17 cell development, IL-6 and TGF-β
are key factors for the generation of Th17 cells from naïve T cells. On the other hand, IL-6 inhibits TGF-β-induced
Keywords:
regulatory T (Treg) cells, which suppress adaptive T cell responses and prevent autoimmunity. Recent studies
Th17
IL-6
suggest that it is an effective approach in the treatment of various autoimmune and inflammatory diseases to
TGF-beta normalize the balance between Treg and Th17 cell development. Here, we review the discovery of the Th17
subset, its properties and relationship with several autoimmune diseases.
Crown Copyright © 2010 Published by Elsevier B.V. All rights reserved.

1. Introduction
CD4+ T cells (Th) are essential regulators of immune responses and
inflammatory diseases. They can be divided into different subsets such
as Th1, Th2 and regulatory T (Treg) cells, whose development is
specified by the transcription factors T-bet, GATA3, and fork head box p3
(Foxp3), respectively (Fig. 1) [1–3]. The development of Th1 cells, which
activate macrophages and are highly effective in clearing intracellular
pathogens, is coupled to the sequential actions of interferon-γ (IFN-γ)
and interleukin-12 (IL-12) [4,5]. Th2 cells, which differentiation is
driven by IL-4, are important for the production of immunoglobulin E
and the clearance of extracellular organisms [6–8]. In addition to these
effector subsets, CD4+ T cells can differentiate into distinct regulatory
subsets (Treg), which express the forkhead/winged helix transcription
factor Foxp3. Transforming growth factor-β1 (TGF-β) promotes the
differentiation of Treg cells, which suppress adaptive T cell responses
and prevent autoimmunity [9,10].
Interleukin 17 (IL-17)-producing T helper cells (Th17) are a new
subset of T helper cells. It has been demonstrated that these Th17 cells
are associated with autoimmunity, such as experimental autoimmune
encephalitis (EAE) and collagen-induced arthritis (CIA) [11–13]. Th17
differentiation is regulated by various cytokines; it is induced by TGF-β
and IL-6 in mice, while IL-1β, TNF-α and IL-23 have been shown to
participate in the expansion of Th17 cells [12,14]. The development of
Th17 cells is negatively regulated by IFN-γ, IL-27 and IL-2, the signals of
which are dependent on Stat1 (IFN-γ and IL-27) and Stat5 (IL-2),
respectively [15–17]. The orphan nuclear receptors, retinoid-related
⁎ Corresponding author.
E-mail address: kishimot@fbs.osaka-u.ac.jp (T. Kishimoto).
orphan receptor γ (RORγ) and RORα, have been identified as the key
transcription factors that determine the differentiation of Th17 lineage
[18,19]. In this review, we discuss the newly identified Th17 lineage and
its relationship in autoimmune and inflammatory diseases.
2. Th17 cells
Th17 cells produce IL-17A (IL-17), IL-17F, IL-22 and TNF-α. The IL-17
family is composed of IL-17A, IL-17B, IL-17C, IL-17D, IL-17E (IL-25), and
IL-17F. IL-17 is a potent inflammatory cytokine [20,21]. Autoimmune
diseases were previously assumed to be associated with dysregulated
Th1 responses. However, IFN-γ deficiency did not attenuate some
models of autoimmune diseases like EAE; on the contrary, IFN-γ
deficiency worsened the disease. It was recently demonstrated that
Th17 cells are dominantly associated with human and mouse
autoimmune diseases such as rheumatoid arthritis (RA), multiple
sclerosis (MS) and inflammatory bowel disease [22–25]. In fact, IL-17
KO mice are resistant to the development of CIA and EAE, and IL-17
blockade by IL-17-blocking antibody prevents the development of EAE
[24,26,27]. These evidence indicates that the regulation of Th17 cell
differentiation and its function is potentially an effective treatment for
autoimmune diseases.
3. Differentiation of Th17 cells
Although initial reports claimed that IL-23 is required for the
generation of Th17 cells from naïve T cells [11,15], it was subsequently
demonstrated that IL-23R is not expressed on naïve T cells. Instead,
IL-23, as well as TNF-α, acts as survival signals for Th17 cells [14,28].
Then, what participates in the development of Th17 cells? It was
found that naive T cells stimulated with TGF-β plus IL-6 secrete large

1567-5769/$ – see front matter. Crown Copyright © 2010 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.intimp.2010.10.004
320 A. Kimura, T. Kishimoto / International Immunopharmacology 11 (2011) 319–322
Fig. 1. Th cell differentiation. Depending on the combination and level of cytokines, naive T cells develop into different lineages: Th1, Th2, Th17 and Treg. Thus, IL-12 induces Th1
responses and IL-4 together with IL-5 and IL-13 favor Th2 differentiation. TGF-β promotes Treg cell development and differentiates naïve T cells into Th17 cells together with IL-6.
amounts of IL-17. The current consensus is that IL-6 induces Th17 cell
differentiation together with TGF-β [12,29]. IL-21, like IL-6, can also
initiate Th17 differentiation combined with TGF-β [30]. However, it
has been indicated that there is an IL-6- and IL-21-independent
pathway in Th17 commitment [31]. The combination of IL-6 and
TGF-β induces the orphan nuclear receptors, retinoid-related orphan
receptor γt (RORγt) and RORα, which are the key transcription
factors in determining the differentiation of the Th17 lineage (Fig. 2)
[18,19]. Stat3 regulates IL-6-induced expression of RORγt and RORα
and IL-17 production [32,33]. In contrast to Stat3 activation, Stat1
activation inhibits the development of Th17 cells. Although IL-6
activates both Stat3 and Stat1, it has been demonstrated that Stat3
activation is maintained while Stat1 activation is suppressed in Th17
cells [31].
There is a negative regulatory system for Th17 cell differentiation.
IL-27 and IFN-γ are responsible for the inhibition of its development in a
Stat1-dependent manner [16,34,35]. IL-27, another IL-12 family
member, uses a receptor complex composed of IL-27R and gp130 to
transduce its signal and activates both Stat1 and Stat3 [36]. Although
both IL-6 and IL-27 transduce their signals via the gp130–JAK–STAT axis,
Fig. 2. Mechanism of Th17 cell differentiation. Th17 cells are induced from naïve T cells
stimulated with TGF-β plus IL-6. ROR t and RORα are identified as the master
transcription factors in Th17 cells. Ahr, known as dioxin receptor, is also induced in
Th17 cells and participates in Th17 cell differentiation through inhibiting Stat1 and
Stat5 activation, which have the inhibitory effect for its development.
IL-6 initiates Th17 commitment dependently on Stat3 activation, and
IL-27 inhibits its development dependently on Stat1 activation.
Additionally, IL-27 augments T-bet, the master transcriptional factor
for Th1 cells [36], which indicates that IL-27 has both pro- and anti-
inflammatory properties in Th cell differentiation. Laurence et al.
demonstrated that IL-2 also inhibits Th17 cell development [17]. They
found that IL-2 cannot inhibit Th17 cell differentiation in Stat5-deficient
T cells, and that there are Stat5 binding sites in the IL-17 promoter
region; these findings suggest that Stat5 serves as a repressor. Thus,
STAT family members activated by various cytokines provide positive
and negative regulation of Th17 cell differentiation (Fig. 2). However,
the mechanisms of the regulation have not been elucidated.
In addition to the aforementioned transcription factors, interferon-
regulatory factor (IRF) 4 and T-bet are two relative new comers to the
scene, and these act as positive and negative regulators of Th17
commitment, respectively [37,38]. Furthermore, while retinoic acid
inhibits Th17 cell development, dioxin, a ligand of Aryl hydrocarbon
receptor, promotes the generation of Th17 cells [39–42]. Ahr is
induced under Th17-polarizing conditions such as in the presence of
TGF-β plus IL-6, and promotes Th17 cell development through
inhibiting Stat1 and Stat5 activation [39]. These findings indicate
that Ahr is one of the important factors in Th17 cell differentiation.
More recently, Ahr promotes the differentiation of type 1 regulatory
T cells and Foxp3(+) regulatory T cells [43,44]. Given that such
nuclear receptors play an important role for Th17 cell differentiation,
the control of nuclear receptor signaling may lead to novel approaches
in the treatment of autoimmune diseases caused by Th17 cells.
4. Th17 cells and autoimmune diseases
Previously, Th1 cells were considered to play a major role in
pathogenesis of CIA and EAE. However, in IFN-γ-deficient mice and
IFN-γ receptor-deficient mice, CIA and EAE symptoms are not
ameliorated but rather exacerbated [45,46]. In contrast, these diseases
are suppressed in IL-17-deficient mice [23,24,26], and are alleviated by
treatment with IL-17-neutralizing antibodies. These results indicate that
in diseases such as CIA and EAE, Th17 cells are actually the major
population in their pathogenesis and the in vivo differentiation and
 A. Kimura, T. Kishimoto / International Immunopharmacology 11 (2011) 319–322
propagation of Th17 cells can be used as an index of these disease
models.
The primary cytokine of Th17 cells, IL-17, exerts potent pro-
inflammatory and joint-destructive activities. IL-17 stimulates the
production of IL-1 and TNF from human macrophages [47], induces IL-6
and IL-8 secretion in synovial fibroblasts [48], and induces upregulation of
the receptor activator of NF-κB ligand (RANKL), an important positive
regulator of osteoclastogenesis [49]. Moreover, targeting IL-17 or IL-17
receptor (IL-17R) in animal models of arthritis effectively controls local
and systemic inflammatory manifestations and blocks cartilage and bone
destruction [24,50]. These data suggest that IL-17 might be a potential
therapeutic target to prevent joint destruction in RA.
Multiple sclerosis (MS) is a chronic inflammatory disease affecting
the central nervous system (CNS) white matter [51]. Activation of
autoreactive CD4+ T cells specific for myelin antigens and differenti-
ation to Th1 effectors were thought to be crucial for the development of
this disease. This widely accepted theory about the pathology of MS was
based on data from experimental autoimmune encephalomyelitis
(EAE), which is induced by administering the myelin sheath framework
protein myelin oligodendrocyte glycoprotein (MOG) peptide together
with an adjuvant and pertussis toxin, a rodent model of MS. However,
the functional role of Th1 cells in EAE has been reconsidered upon the
discovery of Th17 cells. As described above, IL-6 is required for the
generation of Th17 cells. When anti-IL-6 receptor antibodies were
administered immediately after antigen stimulation, the occurrence of
EAE could be suppressed. In EAE models treated with anti-IL-6 receptor
antibodies, no Th17 cells were found in draining lymph nodes or the
spinal cord [52]. On the other hand, the effect of anti-IL-6 receptor
antibodies on Th17 cells and the disease onset was abolished when their
administration was delayed. Thus, IL-6 is required for the initial
differentiation phase for Th17 in the EAE model. These results show
that IL-6 inhibitor therapy is highly effective in suppressing the
occurrence of EAE [52]. These reports indicate that IL-6/Th17 axis is
important for the development of EAE and CIA.
5. Conclusion
T helper cells have been classically separated into two dominant
effector populations; Th1 and Th2 cells. Each T helper cells have specific
lineage-specific transcriptional factors and functional cytokines. How-
ever, accumulating reciprocal modulation evidence between Th17 and
other T helper cell populations suggest that the commitment of T helper
cell lineages is more flexible. For immune homeostasis, it is more
important to modulate the balance between Treg and Th17 cell
development. Additional understanding of the reciprocal courses
between Th17 and other T helper cells including Treg cells will
accelerate progress toward the development of rational strategies for
treating patients with autoimmune and inflammatory diseases.
Acknowledgments
We thank our colleagues in our laboratory for helpful discussion. This
work was supported by the Program for Promotion of Fundamental
Studies in Health Sciences of the National Institute of Biomedical
Innovation and Chugai-Roche Pharmaceutical Co. Ltd., Tokyo, Japan.
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