Research

STAT5 programs a distinct subset of GM-CSF-producing T helper cells that is essential for autoimmune neuroinflammation (Cell Res, Nov 2014)

Sheng W1, Yang F2, Zhou Y3, Yang H2, Low PY4, Kemeny DM4, Tan P5, Moh A6, Kaplan MH7, Zhang Y4, Fu XY8.

11] Cancer Science Institute of Singapore, YLL School of Medicine, National University of Singapore, Singapore [2] Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore.
2Cancer Science Institute of Singapore, YLL School of Medicine, National University of Singapore, Singapore.
3Department of Biochemistry, YLL School of Medicine, National University of Singapore, Singapore.
4Immunology Programme and Department of Microbiology, YLL School of Medicine, National University of Singapore, Singapore.
51] Cancer Science Institute of Singapore, YLL School of Medicine, National University of Singapore, Singapore [2] Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore.
6Departments of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
71] Departments of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA [2] Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
81] Cancer Science Institute of Singapore, YLL School of Medicine, National University of Singapore, Singapore [2] Department of Biochemistry, YLL School of Medicine, National University of Singapore, Singapore [3] Neurobiology Programme, Life Sciences Institute, National University of Singapore, Singapore [4] Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

T helper (TH)-cell subsets, such as TH1 and TH17, 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-γ 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 TH17 or TH1 cells. Consistent with GM-CSF-producing cells being a distinct subset of TH cells, the differentiation program of these cells was distinct from that of TH17 or TH1 cells. We further found that IL-3 was secreted in a similar pattern as GM-CSF in this subset of TH cells. In conclusion, the IL-7-STAT5 axis promotes the generation of GM-CSF/IL-3-producing TH cells. These cells display a distinct transcriptional profile and may represent a novel subset of T helper cells which we designate as TH-GM.

FXY14

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