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

Abstract

Abstract Type I interferons (IFN I) are among the most powerful tools host cells deploy against intracellular pathogens. Their effectiveness is due to both the rapid, directly anti-viral effects of IFN-stimulated gene products, and to the effects of IFN I on responding immune cells. IFN I signaling through its receptor, IFNAR, is tightly regulated at multiple steps in the signaling cascade. Despite the distinct phenotypic changes induced by IFN I in different immune cell types, few studies have addressed the possibility of cell type-specific differences in regulation. In this study, we show that TNFR-associated factor 3 (TRAF3) promotes robust IFNAR signaling specifically in CD4+ T cells by preventing recruitment of the negative regulatory phosphatase PTPN22 to the IFNAR complex. The balance between signals through IFNAR and other differentiating cytokine receptors strongly influences CD4+ T cell differentiation and function during infections. Our work introduces TRAF3 and PTPN22 as newly appreciated regulators key to influencing CD4+ T cell activation by IFN I. Supported by R01 AI123107, T32 AI007260, T32 HL007344, Department of Veterans Affairs