STAT4 is dispensable for Th17 generation but essential for accumulation of pathogenic CD4 T cells in the CNS during EAE

Abstract Multiple Sclerosis is a demyelinating autoimmune disease of the central nervous system (CNS) and is studied using the mouse model experimental autoimmune encephalomyelitis (EAE). Studies utilizing EAE have shown critical pathogenic roles for Th1 and Th17 CD4 T cell subsets. STAT4 is an important Th1 transcription factor that, when activated by IL-12, results in the production of IFNγ, the hallmark Th1 cytokine. Deletion of STAT4 protects mice from EAE; in contrast, deletion of IL-12 and/or IFNγ does not ameliorate disease, revealing gaps in our current understanding of STAT4 biology during EAE. Given that STAT4-/- mice are resistant to EAE, we utilize bone marrow (BM) chimeric mice to provide a physiological environment in which to study the intrinsic role of STAT4 in CD4 T cells during EAE. Interestingly, we find that during EAE the in vivo frequency of STAT4-/- CD4 T cells is greatly reduced in the CNS of BM chimeric mice compared to the wild-type (WT) CD4 T cells. In addition, these STAT4-/- CD4 T cells are able to produce the IL-17 (the hallmark Th17 cytokine) and activate STAT3 via IL-23 signaling (a critical Th17 pathway associated with disease). Although the “pathogenic” Th17 phenotype is intact in STAT4-/- CD4 T cells, this is not sufficient to drive EAE in STAT4-/- mice, therefore, we posit that the defect in CD4 T cell accumulation resulting from either proliferation, cell death, or migration is the critical STAT4 mechanism driving EAE pathogenesis.