LAUSR

Type I interferons (IFNs) are among the most powerful tools that host cells deploy against intracellular pathogens. Their effectiveness is due both to the rapid, directly antiviral effects of IFN-stimulated gene products and to the effects of type I IFN on responding immune cells. Type I IFN signaling through its receptor, IFNAR, is tightly regulated at multiple steps in the signaling cascade, including at the level of IFNAR downstream effectors, which include the kinase JAK1 and the transcriptional regulator STAT1. Here, we found that tumor necrosis factor receptor (TNFR)–associated factor 3 (TRAF3) enhanced the activation of JAK1 and STAT1 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 cytokine receptors influences CD4+ T cell differentiation and function during infections. Our work reveals TRAF3 and PTPN22 as key regulators of CD4+ T cell activation by type I IFNs. Description The adaptor protein TRAF3 prevents a tyrosine phosphatase from blocking type I interferon signaling in T cells. Running interference for interferon Type I interferons (IFNs) are antiviral cytokines produced by infected cells that stimulate an innate immune response through their receptors (IFNARs). Hornick et al. characterized the regulation of type I IFN signaling in CD4+ T cells in the adaptive immune system. Compared with wild-type cells, CD4+ T cells deficient in the adaptor protein TRAF3 showed reduced expression of IFN-responsive genes and reduced receptor-proximal signaling, including decreased activation of the transcriptional regulator STAT1. In the absence of TRAF3, the inhibitory phosphatase PTPN22 was recruited to the IFNAR complex, which blocked STAT1 activation. Treatment of TRAF3-deficient cells with a PTPN22 inhibitor restored their responsiveness to type I IFNs. Together, these data indicate that TRAF3 promotes T cell activation by type I IFNs by preventing the inhibition of receptor signaling.