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Th17 cells: inflammation and regulation
Kazuya Masuda, Tadamitsu Kishimoto
Laboratory of Immune Regulation, Osaka University, World Premier International (WPI)
Immunology Frontier Research Center (IFReC), 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan (KM,
TK)
Published in Atlas Database: February 2014
Online updated version : http://AtlasGeneticsOncology.org/Deep/Th17CellsID20132.html
DOI: 10.4267/2042/54019
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract
IL-17-producing CD4+ T cells (Th17 cells) are understood to be a distinct lineage of CD4+ T helper (Th) cells,
which play an important role in the host defense, tissue inflammation and autoimmunity. The identification of
Th17 cells collapsed the concept of the previously held Th1/Th2 paradigm in infection and autoimmunity.
Recent studies have provided new information on the role of Th17 cells in different autoimmune diseases and the
mechanisms of Th17 cell differentiation. Th17 cells contribute to the exacerbation of autoimmune disease,
whereas they possess a protective aspect against microbes such as bacteria and fungi. This suggests that Th17
cells can be broadly categorized as pathogenic or non-pathogenic. Naïve CD4+ T cells can differentiate into
Th17 cells in synergy with IL-6 and TGF-β, while TGF-β induces regulatory T cells (iTreg), which appear to be
mutually exclusive to Th17 cells. Here we describe the detail molecular mechanism of Th17 cell differentiation,
including recently identified molecules, and discuss different roles of Th17 cells in infection, inflammation and
autoimmunity in a cytokine milieu.
led to the expression of master transcription factor
T-box (Tbx21, T-bet).
In Th2 cells, IL-4 enhanced Stat6 signaling, which
upregulated the transcriptional factor GATA3.
T-bet inhibited Th2 differentiation by attenuating
the function of GATA3, whereas GATA3
contributed to the repression of Th1 cell lineage.
More recently, IL-17-producing T (Th17) cells, as a
third of T cell lineages, have been identified
(Harrington et al., 2005; Park et al., 2005).
Although it was initially demonstrated that IL-23
drives Th17 cell polarization via Stat3 activation in
the absence of IFN-γ, it was generally assumed that
the effect of IL-23 was limited in effector and
memory CD4+ T cells (Oppmann et al., 2000;
Aggarwal et al., 2003; Langrish et al., 2005).
Subsequently, the synergy between TGF-β and IL-6
has been shown to efficiently induce the
development of Th17 cells through Smad and Stat3
pathway, respectively (Bettelli et al., 2006;
Veldhoen et al., 2006). In contrast, TGF-β alone
converted naïve CD4+CD25- T cells into
CD4+CD25+ regulatory T cells (Chen et al., 2003).
1- Introduction
CD4+ T cells play a pivotal role in host defense, but
are also recognized to have pathogenic roles such as
in autoimmunity, asthma, cancer and allergic
responses (Zhu et al., 2010).
On activation by co-stimulatory molecules and
particular cytokines, naïve CD4+ T cells can
differentiate into the distinct lineage of T helper
(Th) cells with different immunological functions,
including Th1, Th2, Th17 cells, and regulatory T
cells (Treg).
Th1 cell polarization was driven by IL-12 and IFNγ, and Th1 cells, which produced IFN-γ, elicited
cell-mediated immunity against intracellular
pathogen, whereas Th2 cells, which secreted IL-4,
IL-5, and IL-13 (Abbas et al., 1996), were induced
by IL-4, and involved in immune responses against
extracellular parasites such as helminthes and
nematodes (Pearce et al., 2002).
Th1 and Th2 cells were shown to be mutually
exclusive (Hwang et al., 2005). In Th1 cells, IL-12
activated Stat4 and induced IFN production, which
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(8)
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Th17 cells: inflammation and regulation
Masuda K, Kishimoto T
The
immunopathogenesis
of
infection,
autoimmunity, and allergy has been extensively
attributed to the concept of Th1/Th2 paradigm.
However, it has been recently reported that CIA and
EAE are exacerbated rather than improved under
inhibition of Th1 cell-inducing condition such as
deficiency of IFN-γR, IL-12 p35 or Stat1 (Iwakura
and Ishigame, 2006). Cua et al. has demonstrated
that IL-23 rather than IL-12 influences the critical
pathogenic effect on autoimmunity such as EAE.
Subsequently, by the same group, it has been shown
that IL-23 promotes the development and expansion
of effector CD4+ T cells, which highly produce IL17, and IL-17 secreted from activated CD4+ T cells
play an important role in various autoimmune
diseases (Langrich et al., 2005).
The balance between Th17 and Treg cells is an
important factor involved in the pathogenesis of
autoimmunity.
Sakaguchi
et
al.
initially
demonstrated that a population of CD4+CD25+ T
cells derived from the thymus, known as nTreg,
exhibited the inhibitory effect in immunity. TGF-β1
is required for the differentiation of both Treg and
Th17 cells, whereas IL-6 suppresses Treg cell
population and drives the development of Th17
cells. This suggests a dichotomy between these
cells (Bettelli et al., 2007). However, it still remains
to be understood how IL-6 in combination with
TGF-β drives Th17 cell differentiation, and which
cytokine milieu makes Th17 cells "pathogenic" in
vivo. In this review, we discuss the mechanism of
Th17 cell differentiation, its plasticity and
pathogenicity in immune regulation, and its link
with inflammatory disease and autoimmunity.
played an important role in Th17 cell differentiation
(Ciofani et al., 2012; Yosef et al., 2013).
BATF, which is a basic leucine zipper (b-Zip)
transcription factor of the AP-1 protein family,
contributed to the generation of Th17 cells
(Schraml et al., 2009). It has recently been reported
that BATF is a multifunctional transcriptional
factor, in which BATF is also required for the
generation of T follicular helper (Tfh) cells but not
Th1 cells and Treg cells (Betz et al., 2010; Ise et al.,
2011). More recently, BATF in cooperation with
IRF-4, which is also essential for the development
of both Th2 and Th17 cells (Brüstle et al., 2009),
has been shown to be involved in the induction of
the IL10, IL-17a, and IL-21 genes in T cells
(Glasmacher et al., 2012; Li et al., 2012; Tussiwand
et al., 2012; Murphy et al., 2013). Although it is
still not clear whether the BATF gene is directly
regulated by Stat3 activation, recent studies have
shown that IL-6 activates the function of
BATF/IRF4 complex (Koch et al., 2013).
More recently, our group has also identified a key
molecule, AT-rich interactive domain 5a (Arid5a),
which is induced under Th17 cell-polarizing
condition. Arid5a deficiency inhibits the
differentiation of Th17 cells (unpublished data).
Our previous report has shown that Arid5a
positively controls IL-6 mRNA through its 3'untranslated region (UTR). IL-6 serum level in
Arid5a deficient mice was dramatically reduced
after LPS injection compared to WT mice, and EAE
was also ameliorated, in which the frequency of
Th17 cell population was inhibited, whereas that of
Th1 cells was enhanced, but not Treg cells (Masuda
et al., 2013).
IL-21 and IL-23 signaling
IL-21 or IL-23 as well as IL-6 enhanced Stat3
activation in Th17 cells via IL-21R or IL-23R
(Muranski et al., 2013). IL-21 has been shown to
have pleiotropic effects on T cells and B cells
(Leonard et al., 2005). IL-21 independent of IL-6
was able to drive naïve T cells into Th17 cells in
the presence of TGF-β1 (Chen et al., 2007).
Nonetheless, IL-6 activates IL-21 expression in
naïve CD4+ T cells via Stat3 activation and IL-21
production is amplified under Th17 cell-inducing
condition through an autocrine-loop (Zhou et al.,
2007; Nurieva et al., 2007).
IL-23 is a heterodimeric cytokine composed of p19
and p40 subunits. IL-23 binds to IL-23R composed
of IL-12Rβ1 and IL23R subunits (Parham et al.,
2002), and mainly activates Stat3 through the Jakstat pathway (Cesare et al., 2009). It was initially
reported that IL-23 contributed to the proliferation
of effector CD4+ T cells (Oppmann et al., 2000).
Subsequently, Parham et al. found that naïve CD4+
T cells did not respond to IL-23, and express little
or no IL-23R.
2- Regulation of Th17 polarization
The mechanism of Th17 differentiation has been
extensively studied with respect to the
transcriptional regulation. Betteli et al. found that
IL-6 but not IL-23 was a potent inducer for Th17
cell differentiation in combination with TGF-β1. It
was initially shown that retinoic acid (RA)-related
orphan receptor γ thymus (Rorγt) was an essential
transcriptional factor for identifying a distinct
lineage of CD4+ T cells (Th17 cells), which
constitutively produced IL-17 in the lamina propria
of the small intestine (Ivanov et al., 2006).
IL-6 signaling
IL-6 mainly activates Stat3 via the Jak-Stat
pathway (Kishimoto, 2005). The role of Stat3 in
Th17 cell differentiation was extensively analyzed
by chromatin immunoprecipitation and massive
parallel sequencing (ChIP-Seq), in which STAT3
bound to the promoter of cytokine and
transcriptional genes including the Rorc, IL-17, IL17F, Ahr and IL-21 genes. Possibly Stat3 also
interacted with the BATF, IRF4, and c-Maf genes
(Durant et al., 2010). These transcriptional factors
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(8)
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Th17 cells: inflammation and regulation
Masuda K, Kishimoto T
Figure 1. Pathogenic Th17 cells were induced by different patterns of cytokines or a chemical, and displayed a unique
character in the expression of possible master regulators and chemokine receptors, respectively. Naïve CD4+ T cells
differentiate into Th17 cells, which mainly express Rorγt, in the presence of IL-6 and TGF-β1. The Th17 cells primarily produce
IL-17, and secret IL-10. IL-23 drives the expansion and proliferation of Th17 cells, and activated Th17 cells secret IL-17, IL-22,
and GM-CSF as well as TGF-β3, whereas the production of IL-10 is inhibited in such a pathogenic Th17 cells. A recent study
has shown that sodium chloride is a strong enhancer of Th17 cells. The high salt-induced Th17 cells display highly pathogenic,
and produce GM-CSF, TNF-α, and IL-2 as well as IL-9. Moreover, it has been reported that there is a direct pathway for the
generation of pathogenic Th17 cells in the presence of IL-6 and TGF-β3. In the Th17 cells, the expression of GM-CSF, IL-23R,
and Tbx21 is highly upregulated, while IL-10 expression is critically attenuated. These pathogenic Th17 cells commonly express
Rorγt, T-bet, and IL-23 R. The Th17 cells under high-salt conditions express serum glucocorticoid kinase 1 (SGK1) downstream
of IL-23R signaling, which critically contributes to the induction of pathogenic Th17 cells. Activated Th17 cells also express some
chemokine receptors, including CCR4, CCR6 and CCR10. However, it still remains to be elucidated what kinds of key molecules
could become master regulators in such a pathogenic Th17 cells.
Rather, IL-23R was induced in the process of Th17
polarization, and Th17 cell differentiation was
promoted by IL-23 (Betteli et al., 2006; Mangan et
al., 2006; Veldhoen et al., 2006). Of note, IL-23 is
one of the most important cytokines, which convert
the Th17 cells differentiated from naïve CD4+ T
cells exposed to IL-6 and TGF-β1 into the
"pathogenic" Th17 (Figure 1). It has been
confirmed that Th17 cells induced by IL-6 and
TGF-β in the absence of IL-23 are not sufficient to
induce EAE (McGeachy et al., 2007), in which IL23 diminished the expression of IL-10 produced
from such "non-pathogenic" Th17 cells. This result
suggests that IL-10 is a key molecule, which
distinguishes pathogenic Th17 from non-pathogenic
types (Figure 2). Consistent with this, Lee et al. and
Kleinewietfeld et al. have demonstrated that IL-10
expression in pathogenic Th17 is suppressed
compared to non-pathogenic ones. Furthermore, IL23 upregulated the Tbx-21 gene (encode T-bet) in
pathogenic Th17 (Lee et al., 2012; Yang et al.,
2009; Kleinewietfeld et al., 2013). However, it
must be further investigated which molecules are
critical for the generation and stability of
pathogenic Th17 under IL-23 signaling or other
pathways (Figure 1).
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(8)
TGF-β signaling
Transforming growth factor β (TGF-β) has complex
roles in cell growth and development (O'Kane and
Ferguson, 1997). TGF-β as well as IL-10 negatively
regulates immune responses including autoimmune
disease and inflammation (Letterio and Roberts,
1998; Moore et al., 2001). It is currently understood
that there are at least three mammalian TGF-β
isoforms (TGF-β1, 2, and 3). TGF-β is an essential
factor for the generation of CD4+ CD25+ regulatory
T cells (iTreg), which express the forkhead/winged
helix transcription factor Foxp3 (Chen et al., 2003;
Batteli et al., 2006; Hori et al., 2003). Notably, IL-2
is required for the generation of iTreg (Zheng SG et
al., 2007), whereas IL-2 signaling via Stat5 inhibits
the differentiation of Th17 cells in vivo and in vitro
by ameliorating IL-6 signaling pathway (Liao et al.,
2011; Chen et al., 2011; Laurence et al., 2007).
The TGF-β superfamily activates not only Smaddependent but also Smad-independent pathways
(Derynck and Zhang, 2003). TGFβ1 and TGFβ3
bind type II receptors on T cells, which leads to the
activation of Smad1, 2, 3 and 5, although Smad2
and Smad3 are activated in a different way from the
activation of Smad1 and Smad5 (Derynck and
Zhang, 2003). As mentioned above, TGFβ1
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Th17 cells: inflammation and regulation
Masuda K, Kishimoto T
induced the differentiation of Th17 cells in the
presence of IL-6, although the Th17 cells did not
show the pathogenicity in autoimmunity possibly
due to the elevation of IL-10 production
(McGeachy et al., 2007). Of note, c-Maf, which is
induced by TGF-β signaling (Rutz et al., 2011),
contributes to the generation of "non-pathogenic"
Th17 cells, in which the expressions of Rora,
Runx1, IL-1R1, Ccl6 and TNF-α are suppressed,
whereas the expressions of IL-10, IL-9, Lif and
CTLA-4 are enhanced (Ciofani et al., 2012; Xu et
al., 2009), although it initially has been reported
that c-Maf is required for the differentiation of
Th17 cells (Bauquet, 2009, Nat.Immunol.). Such
recent data may shed light on the question of how
Th17 cells switches from pathogenic into nonpathogenic and vice versa in infection and
autoimmunity (Figure 1), because non-pathogenic
Th17 cells produce more IL-10 than pathogenic
Th17 cells (McGeachy et al., 2007; Lee et al.,
2012).
In contrast, Lee et al. have recently shown that
TGF-β3 directly drives naïve CD4+ T cells into
"pathogenic" Th17 cell in the presence of IL-6 (Lee
et al., 2012). In this report, TGF-β3-induced Th17
cells highly expressed T-bet and IL-23R, and the
expression of IL-10 was suppressed compared with
those of TGF-β1-induced Th17 cells (Figure 1).
TGF-β activated Smad1 and Smad5 rather than
Smad2 and Smad3. These results suggest that
Smad1 and Smad5 pathway might be important for
the generation of pathogenic Th17 but not nonpathogenic cells. Further investigation of the
molecular mechanism of TGF-β3 signaling is able
to lead to immunotherapy specifically targeting
pathogenic Th17 cells.
As mentioned above, IL-2 is a potent suppressor of
Th17 cell generation. TGF-β1 inhibited IL-2
mediated Stat5 signaling (Bright et al., 1997), and
also attenuated the expression of T-bet and
GATA3, which resulted in elimination of Th1 or
Th2 differentiation (Carsten et al., 2007). It has
been also reported that TGF-β1 produced from
CD4+ effector T cells, including Th17 cells, is
essential for the differentiation and stabilization of
Th17 cells (Gutcher et al., 2011). Thus, it seems
that TGF-β1 is essential for initial Th17
polarization in vitro and in vivo. In contrast, it has
been reported that TGF-β signaling is not necessary
for the generation of pathogenic Th17 cells. Rather,
TGF-β1 inhibited the generation of pathogenic
Th17 cells (Ghoreschi et al., 2010).
Aryl hydrocarbon receptor (Ahr) signaling and
other signaling pathways
Aryl hydrocarbon receptor (Ahr) is a key factor for
the development of Th17 and Th22 cells. Ahr,
which normally resides in the cytoplasm, is a
ligand-activated
transcriptional
factor.
On
recognizing products of tryptophan metabolism as
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(8)
natural ligands or toxic dioxins such as TCDD, Ahr
functions as a transcriptional factor. Our group and
two other groups found that Ahr is induced under
Th17 cell polarizing condition, and involved in
autoimmunity including EAE and CIA (Kimura et
al., 2008; Veldhoen et al., 2008; Quintanna et al.,
2008; Nakahama et al., 2011). Recently, our group
also has shown the role of miR132/212 cluster
induced by Ahr in the differentiation of Th17 cells
(Nakahama et al., 2013). Although it still remains
to be understood how Ahr drives Th17 cell
polarization in vivo, we have recently detailed role
of Ahr in immune responses, including the possible
mechanism of Ahr for Th17 cell differentiation
(Nguyen et al., 2013). This was a unique
demonstration
linking
environment
and
autoimmunity. Recently, as an environmental factor
involved in autoimmunity, it has been reported that
high salt diet might lead to autoimmunity, in which
sodium chloride accelerates EAE through induction
of Th17 cells (Kleinewietfeld et al., 2013).
Retinoic acid (RA), a vitamin A metabolite, has
been shown to mediate reciprocal Th17 and Treg
cell differentiation (Mucida et al., 2007). RA with
TGF-β contributed to stabilization of Treg cells,
and negatively regulates Th17 cell differentiation
(Takahashi et al., 2012). In contrast, RA promoted
effector T cells via retinoic acid receptor α (Rora)
in vivo. Thus, RA controls a dichotomy between
Treg and Th17 cells in a concentration-dependent
manner.
The mammalian target of rapamycin (mTOR)
signaling is involved in the maintenance and
proliferation of Th17 cells (Chi et al., 2012). mTOR
signaling is activated by TCR and/or IL-1β
stimulation via Myd88 (Powell et al., 2012; Chang
et al., 2013), in which IRF4 expression was
regulated (Yao et al., 2013). As mentioned above,
the complex of BATF and IRF4 is essential for the
generation of Th17 cells. BATF is rapidly induced
by TCR stimulation, and then BATF and IRF4
plays a synergistic role in setting the initial
transcriptional program, including chromatin
remodeling and cooperation in accessibility of the
transcriptional factors to target genes such as the
IL-17 gene (Ciofani et al., 2012).
IL-27 (a member of the IL-12 family of cytokines)
signaling contributes to inhibition of Th17
differentiation (Pot et al., 2011). IL-27 binds to a
receptor complex composed of WSX1 (IL-27R) and
gp130, and in turn activates both Stat1 and Stat3.
IL-27 also induces IL-10 expression in CD4+ T
cells, whereas IL-27 inhibits IL-17, IL-22, and GMCSF expression through suppression of Rorγt
activation. Thus, IL-27 is a potent negative
regulator of Th17 cell polarization.
Taken together, a large number of transcriptional
factors control Th17 cell differentiation, in which a
balance between the activation of Stat3 and other
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Th17 cells: inflammation and regulation
Masuda K, Kishimoto T
Stat families (Stat1, 4, 5, and 6) may be an
important factor for driving Th17 cell
differentiation. Moreover, it is for future studies to
decipher the molecular circuits and regulatory
networks in the differentiation of CD4+ T cells and
the plasticity between different T cell lineages,
especially Th17 and Treg cells. A recent new
strategy for identifying regulatory networks
controlling Th17 cell differentiation and the
plasticity have shown the existence of novel factors
including the Mina, Fas, Pou2af1, Tsc22d3, and
Fosl2 genes and dynamism among key
transcriptional regulators (Ciofani et al., 2012;
Yosef et al., 2013).
et al., 2008). Infante-Duarte et al. suggested that
effector CD4+ T cells primed by B. burgdorferi
highly produced IL-17 in inflammatory lesions, and
such cell-types were distinct from Th1 and Th2 cell
types (Infante-Duarte et al., 2000). Following this
initial demonstration, Ye at al. reported that IL-17
secreted from CD4+ T cells protected against
Klebsiella pneumonia for host defense.
Role of IL-22 in Th17 cells
IL-22 as well as IL-17 plays a critical role in host
defense and protecting against tissue damage. IL-22
signaling is transmitted through a heterodimeric
receptor complex composed of IL-10R2 and IL22R1 (Kotenko et al., 2001; Xie et al., 2000). IL22R is mainly expressed in epithelial tissues,
including keratinocytes, hepatocytes, and intestinal
and respiratory epithelial cells, but not in immune
cells (Aggawal et al., 2001; Ouyang et al., 2008;
Rutz et al., 2013). The biological functions of IL-22
are known to be protective against infection and
inflammation because IL-22 contributes to tissue
maintenance, repair, and wound healing through the
expression of anti-microbial, antiapototic proteins
and proteins involved in cell proliferation via IL22R in intestinal epithelial cells and goblet cells
(Rutz et al., 2013).
IL-22 plays a protective role against bacterial
infections. Neutralizing IL-22 secreted by the Th17
lineage led to the failure to clear pathogen from
infected lung by K. pneumonia, and in turn the
early death of infected animals (Aujla et al., 2007).
In this report, IL-17A produced from Th17 cells
synergized with IL-22 to protect against bacteria.
3- Role of Th17 cells in
inflammation
It has been established that Th17 cells are critically
involved in the pathogenesis of autoimmunity, gut
inflammation, tissue inflammation and cancer,
whereas Th17 cells contributes to protection against
a variety of bacteria and fungi. Emerging data on
Th17-mediated diseases suggest that different types
of IL-17-producing T cells exist in vivo, which
might be divided into pathogenic or non-pathogenic
Th17 cells.
Th17 cells produce IL-17 (IL-17A), IL-17F, IL17A/F heterodimers, IL-21, IL-22, and GM-CSF as
well as other chemokines such as CXC cytokines
(Korn et al., 2009). In an early study, IL-17A and
IL-22 secreted from activated T cells were
recognized
as
pro-inflammatory
cytokines
(Dumoutier et al., 2000a; Yao et al., 1995, Ouyang
Figure 2. The plasticity between Th17 cells and Treg, and various types of Th17 cells expanded by IL-23. TGF-β1 is
required for the initial Th17 differentiation in the presence of IL-6. The Th17 cells produce IL-17 and IL-10. TGF-β1 also induces
iTreg. In general, the plasticity of Th17 and Treg cells is tightly regulated in normal condition. However, once an antigen induces
inflammation, macrophages and dendritic cells produce IL-23. IL-23 can convert non-pathogenic Th17 cells into pathogenic
ones. In contrast, IL-23 can inhibit the generation of Treg cells. IL-23-induced Th17 cells convert different cytokine- producing
Th17 cells. IL-6 synergized with IL-1 and IL-23 emerges IL-22 and IFN-γ- producing Th17 cells. IL-6 alone is enough to induce
IL-22-producing T cells. IL-23 alone also promoted IFN-γ-producing T cells.
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Masuda K, Kishimoto T
The coexpression of both IL-17 and IL-22 in Th17
cells are important for expression of antimicrobial
peptides, as mentioned above.
The expression pattern of IL-17 and IL-22 in CD4+
T cells, however, varies according to a cytokine
milieu. IL-6 and/or IL-23 induced IL-22 expression
in vitro in the absence of TGF-β (Qu et al., 2013).
In contrast, TGF-β inhibited the expression of IL-22
(Zheng Y et al., 2007), whereas TGF-β is essential
for the differentiation of Th17 in the presence of IL6 (Figure 2). Moreover, IL-6 deficiency did not
affect the frequency of IL-22 cell population in vivo
(Zenewicz et al., 2008). These results suggest that
IL-22 is produced by not only Th17 cells but also
other immune cells. Therefore, not all Th17 cells
might play a protective role for host defense
through IL-22 production.
Likewise, although IL-22 played a protective role in
infection by various kinds of bacteria, including C.
rodentium, M. tuberculosis, and Salmonera
typhimurium, the sources of IL-22 was assumed to
be not from Th17 cells (Zheng et al., 2008; Schulz
et al., 2008; Dhiman et al., 2009). Moreover, NK
cells as well as CD4+ T cells are involved in
protection against IBD by IL-22, whereas IL-17A
contributed to exacerbation of IBD (Zenewicz et al.,
2008). In contrast, IL-22 produced from effector
Th17 cells contributed to promotion of CD-like
experimental colitis (Yen et al., 2006; Strober et al.,
2007). In line with these reports, Ahern et al. has
demonstrated that IL-23 promotes intestinal
inflammation through directly enhancing the
development of effector Th17 cells, which secret
IL-17, IFN-γ and possibly IL-22 (Figure 2).
Moreover, IL-22-expressing Th17 cells transferred
into IL-22 deficient host mice provided protection
against hepatitis, whereas IL-17 had no apparent
role in liver inflammation (Zenewicz et al., 2007).
However, Xu et al. and Nagata et al. have shown
that IL-17 is required for the development of
hepatitis. Although these reports appear to be
contradictory, CD4+ T cells, which dominantly
produce IL-22 rather than IL-17, might be
protective against hepatitis, whereas IL-23-induced
Th17 cells might have the pathogenicity in liver
inflammation. In agreement with this, Zheng Y et
al. has reported that the production of IL-17 and IL22 from Th17 cells is differentially controlled, and
Th17 cells enhanced by IL-23, which produce IL22, are essential for dermal inflammation and
acanthosis.
IL-23/Th17 axis
The IL-23/Th17 axis is clearly involved in various
autoimmune diseases, including rheumatoid
arthritis, multiple sclerosis, psoriasis, and IBD
(Iwakura and Ishigame, 2006). IL-23 plays an
important role in the maintenance and expansion of
Th17 cells, and makes Th17 cells "pathogenic"
(Figure1). As mentioned above, although different
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(8)
types of effector Th17 cells reside in inflammatory
lesions (Figure 2), a growing number of reports
have shown that IL-17 and IL-23 critically
contribute to the pathogenesis of RA, in which IL17A and IL-17F play an important role in joint
inflammation and bone erosion. Arthritis associated
with psoriasis (psoriatic arthritis) is also dependent
on Th17 cells activated by IL-23 (Maeda et al.,
2012).
The elevation of IL-23 and IL-17 were detected in
synovial fluid, synovial tissues and sera of RA
patients but not of osteoarthritis (Alfadhli, 2013).
IL-23 is also pivotal for the onset of EAE (Cua et
al., 2003). IL-23 or IL-23R deficient mice were
resistant to EAE (Awasthi et al., 2009). IL-17A and
IL-17F double knockout mice showed critical
reduction of the development of EAE, whereas the
effect of IL-17F on EAE development is less than
that of IL-17A in mice (Ishigame et al., 2007).
More recently, Kang et al. has reported that IL-17 is
involved in perturbation of the maturation of
oligodendrocyte lineage cells, which might lead to
inflammation and neurodegeneration in MS.
Pathogenic Th17 cells produce GM-CSF (Figure 1),
which is an important cytokine for induction of IL23 in dendritic cells (McGeachy et al., 2011). It has
been reported that neutralizing GM-CSF at the
effector stage results in suppression of the further
development of EAE (El-Behi et al., 2011). Thus,
GM-CSF is also required for the maintenance and
expansion of Th17 cells possibly through the
enhancement of IL-23.
Th17 cells in host defense
Th17 cells were increased at the mucosal sites after
infection (Happel et al., 2005; Mangan et al., 2006).
So far, it has been demonstrated that Th17 cells are
involved in protection against a variety of bacteria
such as Candida albicans, Staphylococcus aureus,
Citrobacter rodentium, Salmonella and Bordetella
pertusis (Peck and Mellins, 2010). However, the
role of IL-17 and Th17 cells in protection against
Asperillus fumigatus and other fungi are diverse
and controversial (Muranski et al., 2013). One of
the reasons is that the inflammatory milieu for the
generation of Th17 cells is different in infection by
different types of fungi, in which macrophages and
dendritic cells recognize different kinds of fungal
pattern recognition receptors (PRRs) such as
Dectin-1, Dectin-2, Mincle and MR, and produce
inflammatory cytokines for Th17 polarization,
including IL-6, IL-1β, TNF-α and IL-23 as well as
GM-CSF (Wüthrich et al., 2012). Zielinski et al.
has reported that by eliciting different cytokines
respectively, C. albicans and S. aureus prime
different types of IL-17-producing T cells "Th17"
cells that produce IFN-γ or IL-10 respectively,
which might be significant for answering the
question of what makes pathogenic or nonpathogenic Th17 cells.
616
Th17 cells: inflammation and regulation
Masuda K, Kishimoto T
differentiation. Zheng has indicated that IL-6 can
convert nTregs into Th17 cells, and other CD4+ T
cells (Zheng, 2013). It is notable that IL-6 plays a
critical role in conversion of Foxp3+ CD4+ T cells
into pathogenic Th17 cells in autoimmune arthritis
(Komatsu et al., 2014). Th17 cell expansion is also
regulated by TGFβ1 secreted from Th17 cells itself
but not Treg cells (Gutcher et al., 2011). Rather, it
seems that high concentration of TGF-β reduces
Th17 cell populations (Zhou et al., 2008).
The concentration of TGF-β1 is one of the
important factors, which drives or inhibits the
differentiation of Th17 cells (Zhou et al., 2008).
High levels of TGF-β1 inhibited Th17 cell
differentiation and enhanced the development of
iTreg through high expression of Foxp3. In such a
cytokine milieu, Foxp3 induced by TGF-β
interacted with Rorγt, and in turn antagonized the
function of Rorγt in CD4+ T cells, in which the
expression of IL-23R, IL-22 and IL-17 was
repressed (Zhou and Littmann, 2009). In contrast, at
low concentrations, TGF-β1 was helpful for the
generation of Th17 cells in synergy with IL-6 or IL21 (Zhou et al., 2008), although it is still not clear
how IL-6 or IL-21 overcomes the inhibitory effect
of Foxp3 on Rorγt function. Runx-1 controls the
differentiation of Th17 cells thorough binding both
Foxp3 and Rorγt (Zhang et al., 2008). The
interaction of Runx-1 with Rorγt promoted the
transcription of the IL-17 gene, whereas Foxp3
inhibited Rorγt- and Runx-1-induced IL-17
expression by binding to Runx-1 (Zhang et al.,
2008), suggesting that the role of Runx-1 is also
dependent on the concentration of TGF-β1.
Th17 cells in cancer
The role of Th17 cells in cancer displays
complexity in various types of tumor immunity.
Although it seems that the pathogenic role of IL-23induced Th17 cells has been consistently
documented in autoimmunity, Th17 cells in cancer
display both anti-tumorigenic and pro-tumorigenic
functions (Zou and Restifo, 2010). Administration
of IL-23 and IL-23-producing dendritic cells, has
been reported to inhibit tumor growth (Kaiga et al.,
2007; Hu et al., 2006), whereas IL-23 has been
shown to promote tumor incidence and growth
(Langowski et al., 2006). The role of IL-17 in
tumor immunity is also controversial, although the
source of IL-17 is not only Th17 cells, but also
other types of T cells, including CD8+ T cells
(known as Tc17 cells) and Rorγt+ Foxp3+ T cells
(Li and Boussiotis, 2013). IL-17 enhanced tumor
growth through the promotion of tumor
vasculization, especially in some immune-deficient
mice (Zou and Restio, 2010). In contrast, in
immunocompetent mice, IL-17 played a protective
role against tumor growth (Benchetrit et al., 2002;
Kryczek et al., 2009; Hirahata et al., 2001).
Although Th17 cells are present in tumor
microenvironment, the number of Th17 cells
represents a minor population of effector T cells
(Kryczek et al., 2007), suggesting that the
frequency of Th17 cell population is tightly
regulated in tumor immunity. The number of Treg
and Th17 cells inversely correlates in the same
tumor (Zou and Restifo, 2010). It has also been
reported that, in the microenvironment of ulcerative
coloitis (UC) and associated colon cancer, not only
Th17 cells but also IL-17+Foxp3+ T cells are
detected (Kryczek et al., 2011). Thus, the character
of IL-17-producing CD4+ T cells might be
classified more precisely in the context of tumor
immunity.
Balance between Th17 cells and Treg in
autoimmunity
It seems that there is no doubt that Treg cells play a
critical suppressive role in immune responses in
vitro and in vivo (Shevach et al., 2009; Vignali et
al., 2008). Treg cells are a potent inducer of IL-10
and TGF-β1, resulting in suppression of effector T
cell functions. However, the balance between Th17
and Treg cells in vivo is dependent on the context
of inflammatory disease. The existence of Treg
cells does not always suppress the function of Th17
cells. Treg promoted Th17 cell development
through IL-2 regulation rather than control of
TGFβ1 (Pandiyan et al., 2011; Chen et al., 2011).
IL-2 is a critical cytokine in deciding a dichotomy
between Th17 and Treg cells. Treg cells induced by
IL-2 combined with TGF-β or all-trans retinoic
acid, were resistant to Th17 cells (Muchida et al.,
2007; Zheng et al., 2008; Zhou et al., 2010).
Conversely, IL-6 is a strong inducer of Th17 cells
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(8)
4- Therapy (treatment of Th17dependent autoimmunity)
A great number of recent studies have revealed that
the biology of Th17 cells in mice is broadly
common with phenomena in humans (Tesmer et al.,
2008; Jong et al., 2010). Th17 cells in humans play
an important role in the pathogenesis of rheumatoid
arthritis, psoriasis, asthma, inflammatory bowel
disease (IBD) and transplantation rejection.
Accordingly, blocking pro-inflammatory cytokines,
including IL-6, IL-1β, IL-23, and IL-17 as well as
GM-CSF, will lead to the abatement of tissue
inflammation, gut inflammation and autoimmunity.
Several anti-IL-17A monoclonal antibodies,
including secukinumab and ixekizumab, and antiIL-17A receptor monoclonal antibody, brodalumab
have been treated to patients in the process of phase
II clinical trials (Kellner et al., 2013). Secukinumab
is most likely to be clinically efficacious in RA. An
anti-IL-1β monoclonal antibody, gevokizumab is
currently being investigated in a Phase â…¡ clinical
program.
An
anti-IL-12/IL-23
monoclonal
antibody, usutekinumab has been demonstrated the
high efficacy in the treatment of patients with
617
Th17 cells: inflammation and regulation
Masuda K, Kishimoto T
psoriasis (Krueger et al., 2007). An anti-GM-CSF
monoclonal antibody, mavrilimumab for treatment
of rheumatoid arthritis has shown promising results
under phase II clinical trial (Burmester et al., 2013).
In the future, emerging data will establish the
efficacy of these monoclonal antibodies against
several autoimmune diseases such as rheumatoid
arthritis.
IL-6 is involved in the initial differentiation of
Th17 cells (Betteli et al., 2006). In mice, blockade
of IL-6 pathway has been shown to result in a
decrease of the frequency of Th17 cell population
(Nowell et al., 2009; Serada et al., 2009). A
humanized
anti-IL-6
receptor
antibody
(Tocilizumab, TCZ) displayed a remarkable
protective effect in patients with rheumatoid
arthritis as well as Castleman's disease and juvenile
idiopathic arthritis (Genovese et al., 2008; Tanaka
et al., 2012). Although the biological effect of TCZ
on human autoimmune disease is complex (Tanaka
et al., 2013), Samon et al. have demonstrated TCZ
affects the IL-6/Th17 axis in patients with
rheumatoid arthritis, in which the ratio of Th17
cells to Treg cells was significantly reduced.
Therefore, administration of IL-6 blockade (TCZ)
might be highly efficacious against not only such
diseases as mentioned above, but also Th17 celldependent diseases, including IBD and psoriasis,
and cancer.
On the contrary, although elevation of IL-6 level in
inflammatory lesions leads to the exacerbation of
autoimmunity, it remains to be understood why IL6 is overproduced in autoimmune disease such as
rheumatoid arthritis. A recent report has shown that
posttranscriptional regulation of IL-6 production is
essential for immune homeostasis. Zc3h12a (known
as Regnase-1, MCPIP) constitutively degrades level
of IL-6 mRNA trough binding to its 3'UTR,
whereas Zc3h12a deficiency led to spontaneous
autoimmunity (Matsushita et al., 2009). Moreover,
our recent study has shown that Arid5a controls IL6 level in vivo through stabilization of IL-6 mRNA.
Arid5a deficient mice are resistant to EAE, in
which the frequency of Th17 cell population is
dramatically reduced (Masuda et al, 2013, PNAS).
Notably, Arid5a counteracted the destabilization
effect of Zc3h12a (Masuda et al., 2013).
Consequently, imbalance between Arid5a and
Zc3h12a in vivo might be involved in
autoimmunity. Given that administration of TCZ is
efficacious against several autoimmune diseases,
the monoclonal antibody targeting Arid5a might be
also clinically useful.
Concluding remarks
Since IL-17-producing CD4+ T cells have been
shown to be involved in various types of
inflammatory diseases, our understanding of the
pathogenesis of such diseases as rheumatoid
arthritis, multiple sclerosis, and psoriasis, has been
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(8)
dramatically improved since the original concept of
a Th1/Th2 paradigm. However, emerging data on
Th17 cells have revealed that IL-17-producing
CD4+ T cells are not simple cell population. Th17
cells are classified into pathogenic or nonpathogenic ones. IL-23 is a critical factor, which
enhances the pathogenecity of Th17 cells. Recent
data suggests that TGF-β3 and sodium chloride as
well as IL-23 are involved in the generation of
pathogenic Th17 cells. In contrast, TGFβ1 secreted
from Treg cells inhibits the conversion into
pathogenic Th17 cells by attenuating IL-23
production from activated macrophages and
dendritic cells, whereas TGF-β1 is essential for the
initial induction of Th17 cells. Moreover, the
concentration of TGFβ1 is essential for the
plasticity of Th17 and Treg cells. Taken together,
Th17 cells play a pathogenic or protective role in
infection and inflammatory disease in an antigendependent manner. Consequently, to identify which
molecules and signaling pathways are critical for
the generation of pathogenic Th17 cells, will lead to
the development of more efficacious therapeutic
drugs for Th17 cell-dependent inflammatory
disease.
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Atlas Genet Cytogenet Oncol Haematol. 2014; 18(8)
This article should be referenced as such:
Masuda K, Kishimoto T. Th17 cells: inflammation and
regulation. Atlas Genet Cytogenet Oncol Haematol. 2014;
18(8):611-623.
623