TRAF3 Regulates IL-6 Receptor Signaling in T Cells Through the Phosphatase PTPN22

Abstract IL-6 is an important signal three cytokine for T helper 17 (Th17) and T follicular helper (Tfh) differentiation. Previous work has suggested a possible role for TRAF3 in the function and/or differentiation of these two subsets, but no direct studies have yet been performed. In this study, we examine the role of TRAF3 in IL-6R signaling in T cells. TRAF3 regulates IL-2R and type I interferon receptor signaling in T cells by altering recruitment of the phosphatases PTPN2 and PTPN22, respectively. B cell TRAF3 curtails IL-6R signaling by recruiting PTPN22, thus we hypothesized that TRAF3 regulates T cell IL-6R signaling through a PTPN22-dependent mechanism. We investigated the role of T cell TRAF3 using a TRAF3-deficient human T cell lymphoma line and a T cells from a T cell-specific TRAF3 knockout mouse (T-Traf3−/−). We found reduced IL-6-induced STAT1 and STAT3 activation in human and mouse T cells. STAT1 and STAT3 activation are both required for full differentiation of mouse Tfh cells, whereas STAT3 is required for and STAT1 antagonizes Th17 differentiation. Interestingly, in vitrodifferentiation of naïve CD4 T cells to Th17 cells was not affected by TRAF3 deficiency. To determine the mechanism by which TRAF3 promotes STAT1 and STAT3 activation in response to IL-6R signaling, we treated WT and Traf3−/−T cells with IL-6 in the presence of PTPN22 inhibitor or vehicle control. We found that PTPN22 inhibition restored activation of STAT3, but did not restore activation of STAT1, suggesting different mechanisms of regulation. Together these data implicate TRAF3 in regulation of IL-6R signaling in a partly PTPN22-dependent manner, lending an additional level of understanding to TRAF3 regulation of Th17 and Tfh differentiation. Supported by NIH R01 AI123107, R01 AI162656, T32 AI007260