Requirement for the basic helix-loop-helix transcription factor Dec2 in initial TH2 lineage commitment

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Abstract

How naïve CD4 ⁺ T cells commit to the T helper type 2 (T _H2) lineage is poorly understood. Here we show that the basic helix-loop-helix transcription factor Dec2 is selectively expressed in T _H2 cells. CD4 ⁺ T cells from Dec2-deficient mice exhibits defective T _H2 differentiation in vitro and in vivo in an asthma model and in response to challenge with a parasite antigen. Dec2 promotes interleukin 4 (IL-4), IL-5 and IL-13 expression during early T _H2 differentiation, and directly binds to and activates transcription of the Junb and Gata3 genes. As GATA3 induces Dec2 expression, these findings also indicate a feed-forward regulatory circuit during T _H2 differentiation.

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Most cited references 31

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T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma.

Xuexian O. Yang, Bhanu P. Pappu, Roza Nurieva … (2008)

T cell functional differentiation is mediated by lineage-specific transcription factors. T helper 17 (Th17) has been recently identified as a distinct Th lineage mediating tissue inflammation. Retinoic acid receptor-related orphan receptor gamma (ROR gamma) was shown to regulate Th17 differentiation; ROR gamma deficiency, however, did not completely abolish Th17 cytokine expression. Here, we report Th17 cells highly expressed another related nuclear receptor, ROR alpha, induced by transforming growth factor-beta and interleukin-6 (IL-6), which is dependent on signal transducer and activator of transcription 3. Overexpression of ROR alpha promoted Th17 differentiation, possibly through the conserved noncoding sequence 2 in Il17-Il17f locus. ROR alpha deficiency resulted in reduced IL-17 expression in vitro and in vivo. Furthermore, ROR alpha and ROR gamma coexpression synergistically led to greater Th17 differentiation. Double deficiencies in ROR alpha and ROR gamma globally impaired Th17 generation and completely protected mice against experimental autoimmune encephalomyelitis. Therefore, Th17 differentiation is directed by two lineage-specific nuclear receptors, ROR alpha and ROR gamma.

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STAT3 regulates cytokine-mediated generation of inflammatory helper T cells.

Xuexian O. Yang, Athanasia Panopoulos, Roza Nurieva … (2007)

Interleukin-17 (IL-17)-producing helper T (TH) cells, named as TH(IL-17), TH17, or inflammatory TH (THi), have been recently identified as a novel effector lineage. However, how cytokine signals mediate THi differentiation is unclear. We found that IL-6 functioned to up-regulate IL-23R and that IL-23 synergized with IL-6 in promoting THi generation. STAT3, activated by both IL-6 and IL-23, plays a critical role in THi development. A hyperactive form of STAT3 promoted THi development, whereas this differentiation process was greatly impaired in STAT3-deficient T cells. Moreover, STAT3 regulated the expression of retinoic acid receptor-related orphan receptor gamma-T (RORgamma t), a THi-specific transcriptional regulator; STAT3 deficiency impaired RORgamma t expression and led to elevated expression of T-box expressed in T cells (T-bet) and Forkhead box P3 (Foxp3). Our data thus demonstrate a pathway whereby cytokines regulate THi differentiation through a selective STAT transcription factor that functions to regulate lineage-specific gene expression.

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Author and article information

Journal

Journal ID (nlm-journal-id): 100941354

Journal ID (pubmed-jr-id): 21750

Journal ID (nlm-ta): Nat Immunol

Title: Nature immunology

ISSN (Print): 1529-2908

ISSN (Electronic): 1529-2916

Publication date Nihms-submitted: 5 October 2009

Publication date (Electronic): 1 November 2009

Publication date (Print): December 2009

Publication date PMC-release: 1 June 2010

Volume: 10

Issue: 12

Pages: 1260-1266

Affiliations

[1 ] Department of Immunology, MD Anderson Cancer Center, Houston, TX 77030

[2 ] Faculty of Allied Health Sciences, Thammasat University, Pathum-thani 12121, Thailand

[3 ] Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892

[4 ] College of Basic Medicine, Wuhan University, Wuhan, Hubei 430070, China

[5 ] Insittue of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China

Author notes

[6 ]Correspondance should be addressed to C.D. ( cdong@ 123456mdanderson.org ), X.O.Y ( xoyang@ 123456mdanderson.org ) or B.S. ( bsun@ 123456sibs.ac.cn )

Article

Manuscript ID: nihpa150141

DOI: 10.1038/ni.1821

PMC ID: 2784129

PubMed ID: 19881507

SO-VID: ba5eed56-1e8b-4b59-b274-72cadbcfe147

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