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

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.

BATF-dependent IL-7RhiGM-CSF+ T cells control intestinal graft-versus-host disease

“…While pathogenic Th17 cells were shown to be driven by IL-23 (30), GM-CSF + T cell-promoting signals are less well defined. Recently, IL-7 was described to control the formation of murine GM-CSF + T cells in a STAT5-dependent manner (20,31). Importantly, we found that the IL-7-driven GM-CSF + T cell pool in vitro was diminished in the absence of BATF.…”

“…Having shown that BATF identified to control the GM-CSF + donor T cell pool in vivo, we studied whether IL-7-driven GM-CSF + T cell formation was affected in the absence of BATF (20). While IL-7R/Il7r expression kinetics was unaltered in vitro, the pool of IL-7-induced GM-CSF + T cells was diminished in the absence of BATF after 5 days of culture ( Figure 8A, and Supplemental Figure 8, A and B).…”

AMP-Activated Protein Kinase Suppresses Autoimmune Central Nervous System Disease by Regulating M1-Type Macrophage–Th17 Axis

“…Th17 cells expressing GM-CSF have been shown to be highly encephalitogenic (28,45). Although GM-CSF-producing Th cells have previously been identified to serve a nonredundant function in the initiation of autoimmune inflammation (46), a study by Sheng et al (49) reported that the differentiation of GM-CSF-producing cells from naive CD4 + T cells is distinct (ThGM) from that of Th1 and Th17 cells. At present, we cannot comment if AMPK is playing a direct or indirect role in controlling distinct ThGM cell differentiation; however, a significant increase in GM-CSF + CD4…”

IL-21 Exacerbates Autoimmune Myositis by Enhancing the Accumulation of GM-CSF–Producing γδ T Cells in the Muscle

“…In addition, it has been shown that IL-7-induced Stat5 activation promotes the development of GM-CSF-producing CD4 + T cells and causes severe EAE (7). Moreover, GM-CSF is shown to be produced by gdT cells during the development of EAE (8).…”