Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, United States.
Front Immunol. 2018 Oct 22;9:2412. doi: 10.3389/fimmu.2018.02412. eCollection 2018.
Follicular helper T (T) cells represent a highly specialized CD4 T cell subpopulation that supports the generation of germinal centers (GC) and provides B cells with critical signals promoting antibody class switching, generation of high affinity antibodies, and memory formation. T cells are characterized by the expression of the chemokine receptor CXCR5, the transcription factor Bcl-6, costimulatory molecules ICOS, and PD-1, and the production of cytokine IL-21. The acquisition of a T phenotype is a complex and multistep process that involves signals received through engagement of the TCR along with a multitude of costimulatory molecules and cytokines receptors. Members of the Tumor necrosis factor Receptor Associated Factors (TRAF) represent one of the major classes of signaling mediators involved in the differentiation and functions of T cells. TRAF molecules are the canonical adaptor molecules that physically interact with members of the Tumor Necrosis Factor Receptor Superfamily (TNFRSF) and actively modulate their downstream signaling cascades through their adaptor function and/or E3 ubiquitin ligase activity. OX-40, GITR, and 4-1BB are the TRAF-dependent TNFRSF members that have been implicated in the differentiation and functions of T cells. On the other hand, emerging data demonstrate that TRAF proteins also participate in signaling from the TCR and CD28, which deliver critical signals leading to the differentiation of T cells. More intriguingly, we recently showed that the cytoplasmic tail of ICOS contains a conserved TANK-binding kinase 1 (TBK1)-binding motif that is shared with TBK1-binding TRAF proteins. The presence of this TRAF-mimicking signaling module downstream of ICOS is required to mediate the maturation step during T differentiation. In addition, JAK-STAT pathways emanating from IL-2, IL-6, IL-21, and IL-27 cytokine receptors affect T development, and crosstalk between TRAF-mediated pathways and the JAK-STAT pathways can contribute to generate integrated signals required to drive and sustain T differentiation. In this review, we will introduce the molecular interactions and the major signaling pathways controlling the differentiation of T cells. In each case, we will highlight the contributions of TRAF proteins to these signaling pathways. Finally, we will discuss the role of individual TRAF proteins in the regulation of T cell-dependent humoral responses.
滤泡辅助 T(T)细胞是一种高度特化的 CD4 T 细胞亚群,它支持生发中心(GC)的生成,并为 B 细胞提供关键信号,促进抗体类别转换、高亲和力抗体的产生和记忆形成。T 细胞的特征是表达趋化因子受体 CXCR5、转录因子 Bcl-6、共刺激分子 ICOS 和 PD-1,并产生细胞因子 IL-21。获得 T 表型是一个复杂的多步骤过程,涉及到通过 TCR 结合以及多种共刺激分子和细胞因子受体接收到的信号。肿瘤坏死因子受体相关因子(TRAF)成员是参与 T 细胞分化和功能的主要信号转导介质之一。TRAF 分子是物理上与肿瘤坏死因子受体超家族(TNFRSF)成员相互作用的典型衔接分子,并通过其衔接功能和/或 E3 泛素连接酶活性主动调节其下游信号级联反应。OX-40、GITR 和 4-1BB 是 TRAF 依赖性 TNFRSF 成员,它们与 T 细胞的分化和功能有关。另一方面,新出现的数据表明,TRAF 蛋白也参与 TCR 和 CD28 的信号转导,这些信号转导提供了导致 T 细胞分化的关键信号。更有趣的是,我们最近表明,ICOS 的细胞质尾部包含一个保守的 TANK 结合激酶 1(TBK1)结合基序,该基序与 TBK1 结合的 TRAF 蛋白共享。在 ICOS 下游存在这个 TRAF 模拟信号模块是介导 T 分化成熟步骤所必需的。此外,来自白细胞介素 2(IL-2)、白细胞介素 6(IL-6)、白细胞介素 21(IL-21)和白细胞介素 27 细胞因子受体的 JAK-STAT 途径会影响 T 细胞的发育,TRAF 介导的途径和 JAK-STAT 途径之间的串扰可以有助于产生驱动和维持 T 细胞分化所需的综合信号。在这篇综述中,我们将介绍控制 T 细胞分化的分子相互作用和主要信号通路。在每种情况下,我们将强调 TRAF 蛋白对这些信号通路的贡献。最后,我们将讨论单个 TRAF 蛋白在调节 T 细胞依赖性体液反应中的作用。
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