The Transcription Factors T-bet and Runx Are Required for the Ontogeny of Pathogenic Interferon-γ-Producing T Helper 17 Cells

被引：168

作者：

Wang, Yan ^{[1
]}

Godec, Jernej ^{[2
,3
]}

Ben-Aissa, Khadija ^{[1
]}

Cui, Kairong ^{[4
]}

Zhao, Keji ^{[4
]}

Pucsek, Alexandra B. ^{[5
]}

Lee, Yun Kyung ^{[6
]}

Weaver, Casey T. ^{[6
]}

Yagi, Ryoji ^{[7
]}

Lazarevic, Vanja ^{[1
]}

机构：

[1] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA

[2] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA

[3] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

[4] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA

[5] Johns Hopkins Univ, Sch Med, Baltimore, MD 21231 USA

[6] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA

[7] Chiba Univ, Grad Sch Med, Dept Immunol, Chiba 2608670, Japan

来源：

IMMUNITY | 2014年 / 40卷 / 03期

关键词：

IFNG GENE-EXPRESSION; HUMAN TH17 CELLS; ROR-GAMMA; T(H)17 CELLS; LINEAGE; DIFFERENTIATION; PLASTICITY; CYTOKINE; FOXP3; ENCEPHALOMYELITIS;

D O I：

10.1016/j.immuni.2014.01.002

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

T helper 17 (Th17) cells can give rise to interleukin-17A (IL-17A)- and interferon (IFN)-gamma-double-producing cells that are implicated in development of autoimmune diseases. However, the molecular mechanisms that govern generation of IFN-gamma-producing Th17 cells are unclear. We found that coexpression of the Th1 and Th17 cell master transcription factors, T-bet and retinoid-related orphan receptor gamma-t (ROR gamma t), respectively, did not generate Th cells with robust IL-17 and IFN-gamma expression. Instead, development of IFN-gamma-producing Th17 cells required T-bet and Runx1 or Runx3. IL-12-stimulated Th17 cells upregulated Runx1, which bound to the Ifng locus in a T-bet-dependent manner. Reciprocally, T-bet or Runx1 deficiency or inhibition of Runx transcriptional activity impaired the development of IFN-gamma-producing Th17 cells during experimental autoimmune encephalomyelitis, which correlated with substantially ameliorated disease course. Thus, our studies identify a critical role for T-bet and Runx transcription factors in the generation of pathogenic IFN-gamma-producing Th17 cells.

引用

页码：355 / 366

页数：12

共 39 条

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