Generation of pathogenic TH17 cells in the absence of TGF-β signalling

被引：1170

作者：

Ghoreschi, Kamran ^{[1
]}

Laurence, Arian ^{[1
]}

Yang, Xiang-Ping ^{[1
]}

Tato, Cristina M. ^{[2
]}

McGeachy, Mandy J. ^{[2
]}

Konkel, Joanne E. ^{[3
]}

Ramos, Haydee L. ^{[1
]}

Wei, Lai ^{[1
]}

Davidson, Todd S. ^{[4
]}

Bouladoux, Nicolas ^{[5
]}

Grainger, John R. ^{[5
]}

Chen, Qian ^{[4
]}

Kanno, Yuka ^{[1
]}

Watford, Wendy T. ^{[1
]}

Sun, Hong-Wei ^{[6
]}

Eberl, GerRard ^{[7
]}

Shevach, EthanM. ^{[4
]}

Belkaid, Yasmine ^{[5
]}

Cua, Daniel J. ^{[2
]}

Chen, WanJun ^{[3
]}

O'Shea, John J. ^{[1
]}

机构：

[1] NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA

[2] Merck Res Labs, Palo Alto, CA 94304 USA

[3] Natl Inst Dent & Craniofacial Res, Mucosal Immunol Unit, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA

[4] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA

[5] NIAID, Mucosal Immunol Unit, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA

[6] NIAMSD, Biodata Min & Discovery Sect, NIH, Bethesda, MD 20892 USA

[7] Inst Pasteur, Lymphoid Tissue Dev Unit, F-75724 Paris, France

来源：

NATURE | 2010年 / 467卷 / 7318期

关键词：

REGULATORY T-CELLS; GROWTH-FACTOR-BETA; HELPER-CELLS; AUTOIMMUNE ENCEPHALOMYELITIS; PROINFLAMMATORY IL-17(+); TH17; CELLS; IN-VIVO; DIFFERENTIATION; LINEAGE; INFLAMMATION;

D O I：

10.1038/nature09447

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

CD4(+) T-helper cells that selectively produce interleukin (IL)-17 (T(H)17), are critical for host defence and autoimmunity(1-4). Although crucial for T(H)17 cells in vivo(5,6), IL-23 has been thought to be incapable of driving initial differentiation. Rather, IL-6 and transforming growth factor (TGF)-beta 1 have been proposed to be the factors responsible for initiating specification(7-10). Here we show that T(H)17 differentiation can occur in the absence of TGF-beta signalling. Neither IL-6 nor IL-23 alone efficiently generated T(H)17 cells; however, these cytokines in combination with IL-1 beta effectively induced IL-17 production in naive precursors, independently of TGF-beta. Epigenetic modification of the Il17a, Il17f and Rorc promoters proceeded without TGF-beta 1, allowing the generation of cells that co-expressed ROR gamma t (encoded by Rorc) and T-bet. T-bet(+)ROR gamma t(+) T(H)17 cells are generated in vivo during experimental allergic encephalomyelitis, and adoptively transferred T(H)17 cells generated with IL-23 without TGF-beta 1 were pathogenic in this disease model. These data indicate an alternative mode for T(H)17 differentiation. Consistent with genetic data linking IL23R with autoimmunity, our findings re-emphasize the importance of IL-23 and therefore may have therapeutic implications.

引用

页码：967 / U144

页数：6

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