Department of Microbiology and Immunology, University of Iowa, Iowa City, IA 52242, USA.
Graduate Program in Immunology, University of Iowa, Iowa City, IA 52242, USA.
Sci Signal. 2022 Sep 27;15(753):eabn5507. doi: 10.1126/scisignal.abn5507.
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.
I 型干扰素 (IFNs) 是宿主细胞对抗细胞内病原体的最有力工具之一。它们的有效性既归因于 IFN 刺激基因产物的快速、直接抗病毒作用，也归因于 I 型 IFN 对免疫细胞的作用。I 型 IFN 通过其受体 IFNAR 进行信号转导，在信号级联的多个步骤中受到严格调控，包括 IFNAR 下游效应子的水平，其中包括激酶 JAK1 和转录调节剂 STAT1。在这里，我们发现肿瘤坏死因子受体 (TNFR) 相关因子 3 (TRAF3) 通过阻止负调节磷酸酶 PTPN22 募集到 IFNAR 复合物，特异性增强 CD4 T 细胞中 JAK1 和 STAT1 的激活。IFNAR 和其他细胞因子受体信号之间的平衡影响感染期间 CD4 T 细胞的分化和功能。我们的工作揭示了 TRAF3 和 PTPN22 作为 I 型 IFN 激活 CD4 T 细胞的关键调节剂。
