TNF receptor-associated factor (TRAF) signaling network in CD4⁺ T-Lymphocytes

CD4⁺ T helper cells (TH cells), such as T_H1, T_H2, T_H17, T_FH, and T_reg cells, play critical roles in host defense against infection and in the pathogenesis of immune-mediated diseases. Antigen-presenting cells, such as dendritic cells, deliver three kinds of signals essential for the activation, differentiation, and survival of naïve CD4⁺ T cells: the first signal is transmitted through T-cell receptors (TCRs) providing the specificity of the immune response and initiating the earliest signals leading to T-cell activation, the second signal through costimulatory receptors promoting the survival and clonal expansion of the antigen-primed T cells, and the third signal through cytokine receptors directing the differentiation of naïve CD4⁺ T cells into the various T_H subsets. Tumor necrosis factor receptor (TNFR)-associated factors (TRAFs), which are composed of six TRAF proteins (TRAF1-TRAF6) with a conserved C-terminal TRAF domain, are intracellular signaling adaptors that mediate the link between receptor-proximal activation events and intracellular signaling proteins. There is growing evidence that TRAFs recruited to TCRs, costimulatory TNFRs, and cytokine receptors play crucial roles in key signaling events in CD4⁺ T cells and control the lineage commitment, sigfunctionality, and life-and-death decisions of different T_H subsets. In this review, we summarize the TRAFs’ physiological functions in T-cell immunity and the molecular mechanisms by which TRAFs regulate the three signals required for the activation, differentiation, and survival of CD4⁺ T cells and other T-cell subsets.