Transcriptional Regulation of T Helper 17 Cell Differentiation

Yonsei Med J http://www.eymj.org Volume 51 Number 4 July 2010

484

CD4+ T helper (Th) precursor cells are activated by the antigenic stimulation of T

cell receptor (TCR) and are subsequently differentiated into different subsets of

effector Th cells in order to boost the immune responses.

Th1 and Th2 cells are

traditionally thought to be the major subsets generated upon antigenic stimulation

and produce distinct cytokine interferon

(IFN

) and interleukin (IL)-4, which are

then involved in the elimination of intracellular and extracellular pathogens, res-

pectively.

Coordinated cytokine signaling induces the activation of specific

transcription factors to promote lineage-specific cytokine production. While T-

box-containing protein expressed in T cells (T-bet) is activated by IL-12 and IFN

and is exclusively expressed in Th1 cell differentiation,

GATA-binding protein 3

(GATA-3) and c-Maf are required for the chromatin remodeling and direct

activation of Th2 cytokines IL-4, IL-5, and IL-13 for Th2 cell development.

4,5

The

balance of Th1/Th2 cells is thought to be determined by the expression ratio of T-

bet/GATA-3 and is important for inducing autoimmune and allergic immune

responses.

However, the Th1/Th2 paradigm was recently shifted to the Th1/

Th2/Th17/regulatory T (T-reg) hypothesis, a multi-lineage commitment from the

same Th precursor cells.

7,8

regulatory T cells, referred to as regulatory T cells,

express forkhead box P3 (FoxP3) and suppress activated immune responses by

producing transforming growth factor

(TGF

)‚

9,10

whereas Th17 cells induce

Review Article

DOI 10.3349/ymj.2010.51.4.484

pISSN: 0513-5796, eISSN: 1976-2437

Yonsei Med J 51(4):484-491, 2010

Transcriptional Regulation of T Helper 17

Cell Differentiation

Eun Sook Hwang

College of Pharmacy, Division of Life and Pharmaceutical Sciences and Center for Cell Signaling &

Drug Discovery Research, Ewha Womans University, Seoul, Korea.

The third lineage of T helper subsets, Th17, has recently been identified as an IL-

17-producing CD4+ Th cell, and its functions and regulatory mechanisms have

been extensively characterized in immune responses. Functional studies have

provided evidence that Th17 cells are important for the modulation of autoim-

mune responses, such as chronic asthma, rheumatoid arthritis, inflammatory bowel

diseases, and multiple sclerosis. Murine Th17 cell differentiation is enhanced by

the coordinated functions of distinct cytokines including TGF

, IL-6, IL-21, and

IL-23, whereas IL-2, IL-4, IFN

, and IL-27 inhibit its differentiation. In addition,

Th17 cells are controlled by several transcription factors such as ROR

t, IRF4,

BATF, FoxP3, T-bet, PPAR

, E-FABP, and SOCSs. This review focuses on the

functions and regulatory mechanisms of several transcription factors in the control of

Th17 cell differentiation.

Key Words: T helper 17, TGF

, IL-6, transcription factor

Received: March 22, 2010

Corresponding author: Dr. Eun Sook Hwang,

College of Phamacy, Division of Life and

Pharmaceutical Sciences, Center for Cell

Signaling & Drug Discovery Research,

Ewha Womans University,

11-1 Daehyeon-dong, Seodaemun-gu,

Seoul 120-750, Korea.

Tel: 82-2-3277-4369, Fax: 82-2-3277-3760

E-mail: [email protected]

∙The author has no financial conflicts of

interest.

Yonsei University College of Medicine 2010

This is an Open Access article distributed under the

terms of the Creative Commons Attribution Non-

Commercial License (http://creativecommons.org/

licenses/by-nc/3.0) which permits unrestricted non-

commercial use, distribution, and reproduction in any

medium, provided the original work is properly cited.

INTRODUCTION

Regulation of Th17 Differentiation

Yonsei Med J http://www.eymj.org Volume 51 Number 4 July 2010

485

retinoic acid-related orphan receptor

t (ROR

t) -mediated

IL-17 production and control the inflammatory autoim-

mune response.

11,12

The differentiation of Th17 and T-reg

cells requires the activation of TGF

-mediated signaling,

and IL-6 selectively drives Th17 cell differentiation from

TGF

-stimulated Th cells by promoting sequential activa-

tion of IL-21 and IL-23 signaling.

10,13

Here, we review the current understanding of the trans-

cription factors involved in the regulation of Th17 cell dif-

ferentiation, including updates of ROR

t , FoxP3, and

other Th17-specific transcription factors such as interferon

regulatory factor 4 (IRF4), B-cell activating transcription

factor (BATF), peroxisome proliferator activated receptor

(PPAR

), T-bet, and suppressors of cytokine signaling

(SOCS) 3 (Fig. 1).

Many scientists have reported that TGF

and IL-6 are

essential for Th17 cell differentiation.

12,14,15

TGF

, which is

produced by innate immune cells, binds to its specific recep-

tor and induces engagement of TGF

receptor I and II with

subsequent activation of receptor-associated SMADs. Acti-

vated SMADs interact with a variety of transcription factors,

resulting in chromatin remodeling and modulation of gene

transcription of TGF

target genes.

TGF

inhibits signal

Fig. 1. Cytokine signaling and transcription factors in the regulation of Th17 cell differentiation. TCR stimulation activates gene expression of general transcription

factors such as NFAT, AP-1, and NF-κB, and induces Th cell activation and proliferation. BATF is activated upon TCR stimulation and stimulates IL-17 gene

transcription. TGF

stimulation induces both FoxP3 and RORγt (also RORa) activation. High concentrations of TGFb increase FoxP3 through the activation of SMAD4

and subsequently induce TGFb production and simultaneously suppress RORγt activity and Th17 cell differentiation. However, the presence of cytokine IL-6 or IL-21

activates STAT3 and induces gene expression of the IL-21 and IL-23 receptor, activating positive IL-21 autocrine regulation for Th17 cell differentiation. In addition, IL-1

induces IRF4 or epidermal FABP4, which in turn induces IL-17 gene transcription. While T-bet and Ets-1 antagonize RORγt activity and thus function as suppressors of

Th17 cell development, PPARγintrinsically suppresses IL-17 gene transcription by blocking the activation-induced removal of repressor complexes from the IL-17

gene promoter. SOCS1 and SOCS reciprocally modulate Th17 cell differentiation. TCR, T cell receptor; NFAT, nuclear factor of activated T cells; AP, activator protein;

BATF, B cell-activating transcription factor; IL-17, interleukin-17; TGF

, transforming growth factor

; RORγt, retinoic acid-related orphan receptor γt; STAT, signal

transducer and activator of transcription; IRF-4, interferon-inducible factor-4; E-FABP, epidermal-fatty acid-binding protein; PPARγ, peroxisome proliferator activated

receptor γ; SOCS, suppressors of cytokine signaling.

TGF

ββ

- AND IL-6-MEDIATED

TH17 CELL DIFFERENTIATION

Eun Sook Hwang

Yonsei Med J http://www.eymj.org Volume 51 Number 4 July 2010

486

transducer and activator of transcription (STAT5)-medi-

ated IL-2 production in TCR-stimulated T cells

and also

interferes with Th1 and Th2 cell differentiation by inhibiting

expression of master transcription factor T-bet and GATA-

18,19

In addition, TGF

increases FoxP3 expression and

induces generation of T-reg cells.

FoxP3-positive T-reg

cells potently suppress cell proliferation and differentiation

of Th cells by boosting TGF

production.

Overexpres-

sion of TGF

in a T cell-specific manner in mice leads to

the generation of T cells with regulatory functions and pro-

tects IL-2-deficient mice from developing severe systemic

inflammation with autoimmunity.

20,21

However, additional

production of the pro-inflammatory cytokine IL-6 along

with TGF

suppresses FoxP3 expression and T-reg cell

generation and simultaneously induces IL-17 production,

resulting in Th17 cell differentiation.

Consistent with this,

TGF

transgenic mice treated with myelin oligodendrocyte

glycoprotein (MOG) in complete Freund’s adjuvant (CFA)

exhibit substantially increased Th17-mediated immune

responses and aggravated experimental autoimmune encep-

halomyelitis (EAE),

indicating that TGF

plus IL-6 in-

duces the generation of Th17 cells. Despite the importance

of TGF

function in murine Th17 cells, TGF

is dispen-

sable for human Th17 cell differentiation. Instead, human

Th17 cells are induced by stimulation with IL-6, together

with another cytokine such as IL-1, IL-21, or IL-23.

15,22,23

IL-6 is a key factor for inducing human and murine Th17

cell differentiation by activating STAT3 and ROR

tex-

pression. STAT3 activation is induced not only by IL-6 but

also by IL-21 and IL-23.

13,24,25

While STAT3-null cells fail

to express ROR

t and produce a diminished level of IL-

17, retroviral restoration of STAT3 rescues the IL-17 de-

fect.

Although it is still unclear whether STAT3 modula-

tes ROR

t gene transcription, activated STAT3 directly

binds to the STAT-binding sites in the IL-17 gene pro-

moter and increases IL-17 gene transcription.

In addition

to the functional importance of STAT3 activation in Th17

cell differentiation, ROR

t has been identified as a master

regulator of Th17 cell differentiation. Analogous to STAT4-

mediated T-bet in Th1 cells and STAT6-dependent GATA-

3 in Th2 cells, Th17 cells require activation of STAT3 and

subsequent ROR

t induction.

ROR

t , a spliced isoform

of ROR

, is a member of the nuclear receptor superfamily,

and is closely related to the retinoic acid receptor (RAR)

subfamily,

and is required for thymocyte survival and

lymphoid organogenesis.

Deficiency of ROR

t results in

profound Th17 deficiency and protects mice from EAE

development.

Ectopic overexpression of STAT3 in ROR

deficient cells, and vice versa, fails to restore IL-17 produc-

tion.

This suggests that STAT3 and ROR

t may each

regulate the other’s gene transcription and induce IL-17

expression parallel to some extent. More recently, ROR

was reported as a novel Th17-specific transcription factor.

Like ROR

t , ROR

is induced by TGF

plus IL-6 in a

STAT3-dependent manner, and promotes Th17 cell dif-

ferentiation through direct activation of IL-17 gene trans-

cription.

Double deficiency of ROR

t and ROR

results

in complete blockade of IL-17 production and EAE devel-

opment.

IRF4 was originally identified as a GATA-3 inducer in Th2

cell differentiation.

31,32

However, IRF4-null mice exhibit

impaired generation of Th17 cells in response to TGF

and IL-6 and increased resistance to EAE.

In addition,

IRF4-deficient Th cells exhibit an intrinsic defect in the

autocrine IL-21 loop and an increased population of

FoxP3-mediated T-reg cells with no effect on STAT3 acti-

vation and SOCS3 expression.

A more recent report

implies that IRF4 is activated upon IL-1 signaling and is

critical for early Th17 cell differentiation.

Despite the

importance of IRF4 in Th17 cell differentiation, the mole-

cular mechanisms are unclear. The fact that IRF4 interacts

with NFATp to induce IL-4 expression may suggest that

IRF4 modulates NFATp-dependent IL-2 expression, which

is associated with IL-17 production.

36,37

The BATF is a basic leucine zipper (bZIP) transcription

factor and dimerizes with Jun class factors of the activator

protein-1 (AP-1) family.

38-40

BATF is known to function as

a potent inhibitor of AP-1-mediated gene expression via

the phosphorylation of BATF.

40-42

In addition, expression

analysis reveals that BATF is highly expressed in hemato-

poietic cells and is increased in B and T cells by the activa-

tion of NF-

B in response to viral infection or IL-6-sti-

mulation.

43-47

BATF gene transcription is substantially inc-

reased in activated Th cells subsets including Th1, Th2,

and Th17 cells.

Despite its wide expression in all Th1,

Th2, and Th17 cells, BATF-deficiency fails to generate IL-

17 in CD4+ and CD8+ T cells in vitro and in vivo, but

STAT3 AND ROR

γγ

t AS KEY

TRANSCRIPTION FACTORS FOR TH17

CELL DIFFERENTIATION

IRF-4 FUNCTIONS IN IL-21-INDUCED

TH17 CELL DIFFERENTIATION

BATF AS A PROMOTER FOR TH17

CELL DIFFERENTIATION

Regulation of Th17 Differentiation

Yonsei Med J http://www.eymj.org Volume 51 Number 4 July 2010

487

rather increases T-reg cell generation, thus protecting mice

from EAE development.

While the levels of ROR

and

ROR

t expression are not sustained in BATF-deficient

Th17 cells compared with those in wild type (WT) cells,

enforced ROR

t expression is not able to restore IL-17

production in BATF-deficient Th cells. Nevertheless,

BATF synergizes with ROR

t to induce IL-17 expression

through direct interaction with the IL-17 gene promoter.

Many questions regarding BATF, such as whether IL-6-

induced STAT3 activation is affected by BATF deficiency

and whether BATF is required for DNA binding of ROR

or IRF4, remain to be addressed in the future.

Differentiation of FoxP3-directed T-reg cells and ROR

driven Th17 cells has been shown to be triggered by TGF

signaling, but the Th17 differentiation program requires

additional IL-6 or IL-21 cytokine signaling either to switch

off FoxP3 or to switch on ROR

10,11,15

suggesting recipro-

cal regulation of T-reg and Th17 cells during Th cell differ-

entiation. It has been asked whether T-reg can be convert-

ed to Th17 in response to IL-6 and how FoxP3 and ROR

modulate each other’s expression or activity.

30,50,51

Interes-

tingly, FoxP3 and IL-17 are both induced upon TGF

sti-

mulation.

13,52

In addition, FoxP3-positive Th cells produce

IL-17 in the presence of IL-6 through the activation of

ROR

t , whereas FoxP3 antagonizes ROR

t activity in a

manner dependent on SMAD4, suggesting the plasticity of

T-reg cells.

Others also report that FoxP3 inhibits IL-17

expression by antagonizing ROR

t function in a TGF

concentration-dependent manner

or through direct

interaction with ROR

Like the suppressive function of

FoxP3 on IL-17 expression, the Th1-specific transcription

factor T-bet suppresses ROR

t -mediated Th17 cell differ-

entiation.

55-57

Several functional studies indicate that T-bet

suppresses ROR

t expression and Th17 cell differentiation

and further attenuates autoimmune responses.

56,58-62

None-

theless, the mechanism by which T-bet directly or indirectly

inhibits IL-17 expression and whether T-bet antagonizes

ROR

t activity remain to be characterized. In addition, a

T-bet-interacting transcription factor, Ets-1 positively mo-

dulates Th1 cell differentiation but inhibits Th17 cell genera-

tion.

63,64

Ets-1-deficient Th cells exhibit preferential differen-

tiation into Th17 cells and increased IL-22 and IL-23

receptor expression.

Moreover, targeting of Ets-1 by mi-

croRNA miR-326 promotes Th17 differentiation.

Since

there is no apparent interaction between Ets-1 and IL-17

gene promoter, how Ets-1 modulates IL-17 expression

must be defined in the future.

Peroxisome proliferator-activated receptor

(PPAR

) is a

nuclear receptor like ROR

t and ROR

and forms hetero-

dimers with retinoid X receptors (RXRs) to bind to the gene

promoter.

66,67

PPAR

activation upon ligand binding is criti-

cal for the expression of genes such as adiponectin and

fatty acid-binding protein (FABP) (also referred as aP2) in-

volved in adipocyte differentiation and lipid metabolism

68,69

While enforced PPAR

expression induces adipocyte dif-

ferentiation from fibroblasts, PPAR

-deficiency attenuates

white adipose tissue development.

Although PPAR

func-

tions as a master transcriptional regulator for adipocyte

differentiation, the anti-inflammatory activity of PPAR

also well-characterized.

71-73

The anti-inflammatory function

of PPAR

is mediated through the inhibition of both matu-

ration and function of dendritic cells and macrophages.

74,75

More precisely, the ligand-binding domain of PPAR

sumoylated upon ligand activation and prevents the removal

of repressor complexes composed of nuclear receptor core-

pressor and histone deacetylase-3, thus resulting in sustain-

ed repressor complex-induced silencing of pro-inflamma-

tory cytokine genes.

76,77

In addition to the modulation of

macrophage function, PPAR

modulates T cell activity by

inhibiting IL-2 production in T cell receptor-stimulated Th

cells

and by suppressing Th2 cell differentiation.

There-

fore, PPAR

ligands including endogenous and synthetic

agonists such as linoleic acid, prostaglandin J2, and thia-

zolidinediones have been extensively studied due to the

interest in treating inflammatory diseases.

71,80,81

A recent

study demonstrates that PPAR

is an intrinsic suppressor

for Th17 cell generation.

PPAR

activation is thought to

prevents removal of repressor complexes from ROR

gene promoter, thus suppressing ROR

t expression and

ROR

t -induced Th17 cell differentiation in an intrinsic

manner. Moreover, human multiple sclerosis patients are

impressively susceptible to PPAR

-mediated suppression

of Th17 cell development, strongly asserting PPAR

as a

promising target for specific immunointervention in auto-

immune disorders.

In contrast to the suppressive function of adipogenic

PPAR

, epidermal FABP (E-FABP) is characterized as a

positive modulator of IL-17 production in Th cells.

FABP-

deficiency contributes to the protection from EAE devel-

opment,

which has been explained by the reduced level

of pro-inflammatory cytokines in macrophages and

dendritic cells.

Moreover, FABP-deficient Th cells ex-

press increased amounts of PPAR

and subsequently

suppress IL-17 production; however, this can be reversed

by treatment with the PPAR

antagonist, GW9662.

FOXP3, T-BET, AND ETS-1 SUPPRESS

TH17 CELL DIFFERENTIATION

PPAR

γγ

AND E-FABP MODULATE TH17

CELL DIFFERENTIATION

detailed molecular mechanisms of E-FABP have yet to be

characterized.

The SOCS inhibit STAT-mediated cytokine signaling.

86,87

Since SOCS1 suppresses both IFN

- and IL-4-mediated

Th1 and Th2 cell differentiation, genetic ablation of SOCS1

results in unconditional hyperactivation of T cells.

addition, T cell-specific SOCS1-conditional knockout mice

exhibit attenuated Th17 cell generation and induced hyper-

activation of SOCS3 in Th cells,

suggesting that SOCS1

as a transcriptional activator for Th17 cell development.

Activated SOCS3 is known to selectively suppress STAT-3

activation induced by IL-6, granulocyte-colony stimulating

factor (GCSF), and leptin,

90,91

whereas deficiency of

SOCS3 increases TGF

production and simultaneously

enhances Th17 cell development.

27,92

It is also reported that

TGF

inhibits SOCS3 gene transcription and prolongs

STAT3 activation during Th17 cell differentiation.

With the recent reports of the functions of IL-17-producing

Th17 cells in autoimmune responses and the regulatory

mechanisms for Th17 cell differentiation, a new paradigm

of Th cell differentiation has been established. The Th1/

Th2 paradigm is mainly shifted to a Th1/Th2/ Th17/T-reg

program. This review describes the function and potential

mechanisms of transcription factors critical for the regul-

ation of Th17 cell differentiation and also includes inter-

connection among transcription factors such as Th1-

specific T-bet, T-reg-limited FoxP3, and Th17-specific

ROR

t . These transcription factors have prevalent roles in

determining lineage commitment through interaction with

cytokine gene promoters and/or other lineage-specific

transcription factors. Targeting these transcription factors,

as well as signature cytokines, may be beneficial for

controlling several autoimmune diseases, although re-

search is currently underway to identify the detailed me-

chanisms.

This work was supported by the R&D program (A080908)

of KHIDI and partly by the NCRC program (R15-2006-

020) funded by MEST.

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