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

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-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 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.