TRAF3 enhances type I interferon receptor (IFNAR) signaling in T cells through modulation of PTPN22

Abstract

Abstract T cell responses are critical for successful resolution of many infectious and non-infectious challenges. Robust T cell activation and acquisition of effector functions relies on receipt of at least three signals: 1) antigen recognition by the T cell receptor, 2) co-stimulation, and 3) cytokines. TNF receptor-associated factor 3 (TRAF3) is an adapter protein with diverse cell type- and receptor-specific functions, that regulates signals one and two of conventional T cell activation. In this study, we examine the role of TRAF3 in signaling downstream of the potent signal three cytokine, type I interferon (IFN I). Work from our laboratory has shown that in other contexts, TRAF3 regulates cytokine receptor signaling by facilitating association of phosphatases with JAKs at the cytokine receptor. We therefore hypothesize that TRAF3 regulates IFNAR signaling in T cells through affecting recruitment of the phosphatase PTPN22 to the IFNAR complex. We investigate the role of TRAF3 in IFNAR signaling using a TRAF3-deficient human T cell lymphoma line and T cells from a T cell specific TRAF3 knockout mouse (T-Traf3−/−). TRAF3−/− T cells display a marked defect in STAT1 activation, leading to defects in IFN-stimulated gene expression and CXCL10 secretion. We show TRAF3 and PTPN22 association with JAK1 and IFNAR1 upon IFN I stimulation in WT T cells, and increased association of PTPN22 with JAK1 and IFNAR1 in TRAF3−/− T cells. Inhibition of PTPN22 restores IFNAR signaling in TRAF3-deficient cells to near WT levels. Together, these data indicate that TRAF3 modulates IFNAR signaling by modulating PTPN22 association with the IFNAR signaling complex, broadening our understanding of the crucial signals that drive T cell activation and polarization.