STAT4 controls GM-CSF production by both Th1 and Th17 cells during EAE (BA4P.140)

Factors mediating Th1 and Th17 CD4 T cell driven autoimmunity remain unclear. In the mouse model of Multiple Sclerosis, experimental autoimmune encephalomyelitis (EAE), mice genetically deficient in STAT4 are resistant to disease. In contrast, deletion or inhibition of the Th1-associated cytokines IL-12 or IFNγ, which act upstream and downstream of STAT4, respectively, does not ameliorate disease. This highlights a non-canonical role for STAT4 during EAE. Recent reports have indicated that GM-CSF, a cytokine produced by both Th1 and Th17 effector CD4 T cell subsets, is critical for EAE pathogenicity. Importantly, the requirement for STAT4 in mediating GM-CSF production has not yet been investigated. Herein, we demonstrate that STAT4 controls GM-CSF production by both Th1 and Th17 CD4 T cells during EAE, and this is CD4 T cell intrinsic. Furthermore, STAT4 mediates CD4 T cell derived GM-CSF production independently of the cytokines IL-12 and IL-23. Importantly, we show that STAT4 directly interacts with the Csf2 locus in effector CD4 T cells during EAE. Overall, these studies illustrate the previously unrecognized role of STAT4 to regulate GM-CSF production by both Th1 and Th17 effector cell subsets during EAE pathogenesis.