CD4
+ T helper cells (T
H 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, functionality, 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.
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