STAT5 programs a distinct subset of GM-CSF-producing T helper cells that is essential for autoimmune neuroinflammation

被引:153
作者
Sheng, Wanqiang [1 ,2 ]
Yang, Fan [1 ]
Zhou, Yi [3 ]
Yang, Henry [1 ]
Low, Pey Yng [4 ,5 ]
Kemeny, David Michael [4 ,5 ]
Tan, Patrick [1 ,6 ]
Moh, Akira [8 ,9 ]
Kaplan, Mark H. [8 ,9 ]
Zhang, Yongliang [4 ,5 ]
Fu, Xin-Yuan [1 ,3 ,7 ,10 ]
机构
[1] Natl Univ Singapore, YLL Sch Med, Canc Sci Inst Singapore, Singapore 117548, Singapore
[2] Natl Univ Singapore, Fac Sci, Dept Biol Sci, Singapore 117548, Singapore
[3] Natl Univ Singapore, YLL Sch Med, Dept Biochem, Singapore 117548, Singapore
[4] Natl Univ Singapore, YLL Sch Med, Immunol Programme, Singapore 117548, Singapore
[5] Natl Univ Singapore, YLL Sch Med, Dept Microbiol, Singapore 117548, Singapore
[6] Duke NUS Grad Med Sch, Singapore, Singapore
[7] Natl Univ Singapore, Inst Life Sci, Neurobiol Programme, Singapore 117548, Singapore
[8] Indiana Univ, Sch Med, Dept Pediat, Indianapolis, IN 46202 USA
[9] Indiana Univ, Sch Med, Herman B Wells Ctr Pediat Res, Indianapolis, IN 46202 USA
[10] Indiana Univ, Sch Med, Dept Microbiol & Immunol, Indianapolis, IN 46202 USA
基金
英国医学研究理事会;
关键词
T helper cell; experimental autoimmune encephalomyelitis; GM-CSF; IL-7; STAT5; INTERLEUKIN-7; RECEPTOR; TRANSCRIPTION FACTOR; CYTOKINE; DIFFERENTIATION; T(H)17; MICE; ASSOCIATION; RESPONSES; IL-12; GENE;
D O I
10.1038/cr.2014.154
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
T helper (T-H)-cell subsets, such as T(H)1 and T(H)17, mediate inflammation in both peripheral tissues and central nervous system. Here we show that STAT5 is required for T helper-cell pathogenicity in autoimmune neuroinflammation but not in experimental colitis. Although STAT5 promotes regulatory T cell generation and immune suppression, loss of STAT5 in CD4(+) T cells resulted in diminished development of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Our results showed that loss of encephalitogenic activity of STAT5-deficient autoreactive CD4(+) T cells was independent of IFN-gamma or interleukin 17 (IL-17) production, but was due to the impaired expression of granulocyte-macrophage colony-stimulating factor (GM-CSF), a crucial mediator of T-cell pathogenicity. We further showed that IL-7-activated STAT5 promotes the generation of GM-CSF-producing CD4(+) T cells, which were preferentially able to induce more severe EAE than T(H)17 or T(H)1 cells. Consistent with GM-CSF-producing cells being a distinct subset of T-H cells, the differentiation program of these cells was distinct from that of T(H)17 or T(H)1 cells. We further found that IL-3 was secreted in a similar pattern as GM-CSF in this subset of T-H cells. In conclusion, the IL-7-STAT5 axis promotes the generation of GM-CSF/IL-3-producing T-H cells. These cells display a distinct transcriptional profile and may represent a novel subset of T helper cells which we designate as T-H-GM.
引用
收藏
页码:1387 / 1402
页数:16
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