Format

Send to

Choose Destination
Cell Res. 2014 Dec;24(12):1387-402. doi: 10.1038/cr.2014.154. Epub 2014 Nov 21.

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

Author information

1
1] 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.
2
Cancer Science Institute of Singapore, YLL School of Medicine, National University of Singapore, Singapore.
3
Department of Biochemistry, YLL School of Medicine, National University of Singapore, Singapore.
4
Immunology Programme and Department of Microbiology, YLL School of Medicine, National University of Singapore, Singapore.
5
1] 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.
6
Departments of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
7
1] 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.
8
1] 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.

Abstract

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.

PMID:
25412660
PMCID:
PMC4260352
DOI:
10.1038/cr.2014.154
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center