Department of Microbiology and Immunology, The University of Iowa, Iowa City, IA, United States.
Department of Internal Medicine, The University of Iowa, Iowa City, IA, United States.
Front Immunol. 2023 Feb 6;14:1129251. doi: 10.3389/fimmu.2023.1129251. eCollection 2023.
Tumor necrosis factor receptor (TNFR)-associated factor 3 (TRAF3) is an adapter protein with many context-specific functions. Early studies of lymphocyte TRAF3 hinted at TRAF3's importance for T cell function, but elucidation of specific mechanisms was delayed by early lethality of globally TRAF3 mice. Development of a conditional TRAF3-deficient mouse enabled important descriptive and mechanistic insights into how TRAF3 promotes optimal T cell function. Signaling through the T cell antigen receptor (TCR) fails to induce normal proliferation and survival in TRAF3 T cells, and TCR-activated cells and have deficient cytokine production. These defects can be traced to incorrect localization and function of negative regulatory phosphatases acting at different parts of the signaling cascade, as can dysregulated effector responses and memory T cell homeostasis and an enlarged regulatory T cell (Treg) compartment. The important regulatory activity of TRAF3 is also evident at members of the TNFR superfamily and cytokine receptors. Here, we review significant advances in mechanistic understanding of how TRAF3 regulates T cell differentiation and function, through modulation of signaling through the TCR, costimulatory receptors, and cytokine receptors. Finally, we briefly discuss the recent identification of families carrying single allele loss-of-function mutations in , and compare the findings in their T cells with the T cell defects identified in mice whose T cells completely lack T cell TRAF3. Together, the body of work describing TRAF3-mediated regulation of T cell effector function and differentiation frame TRAF3 as an important modulator of T cell signal integration.
肿瘤坏死因子受体（TNFR）相关因子 3（TRAF3）是一种具有多种特定功能的衔接蛋白。早期对淋巴细胞 TRAF3 的研究暗示了 TRAF3 对 T 细胞功能的重要性，但由于全球 TRAF3 小鼠的早期致死性，特定机制的阐明被推迟。TRAF3 条件性缺失小鼠的开发使我们能够深入了解 TRAF3 如何促进 T 细胞功能的优化，这具有重要的描述性和机制性意义。T 细胞抗原受体（TCR）的信号转导不能诱导 TRAF3 T 细胞的正常增殖和存活，并且 TCR 激活的细胞 和 产生缺陷的细胞因子。这些缺陷可以追溯到在信号转导级联的不同部位起作用的负调节磷酸酶的不正确定位和功能，以及失调的效应器反应和记忆 T 细胞稳态 和调节性 T 细胞（Treg）的增大。TRAF3 的重要调节活性也在 TNFR 超家族和细胞因子受体的成员中显而易见。在这里，我们回顾了在 TRAF3 通过调节 TCR、共刺激受体和细胞因子受体的信号转导来调节 T 细胞分化和功能的机制理解方面的重要进展。最后，我们简要讨论了最近在 中发现的携带单等位基因功能丧失突变的家族，并将其 T 细胞中的发现与完全缺乏 T 细胞 TRAF3 的小鼠的 T 细胞缺陷进行了比较。总的来说，描述 TRAF3 介导的 T 细胞效应功能和分化调节的工作为 TRAF3 作为 T 细胞信号整合的重要调节剂提供了框架。
