Tohoku J. Exp. Med., 2015 June, 236(2)

Invited Review

TNF Receptor-Associated Factor (TRAF) Signaling Network in CD4⁺ T-Lymphocytes

TAKANORI SO,¹ HIROYUKI NAGASHIMA¹ and NAOTO ISHII¹

¹Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan

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 nai¨ve 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 nai¨ve 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.

keywords —— CD4⁺ T cells; signalosome; T-cell biology; TNFR; TRAF

© 2015 Tohoku University Medical Press

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Tohoku J. Exp. Med., 2015, 236, 139-154

Correspondence: Takanori So, Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aobaku, Sendai, Miyagi 980-8575, Japan.

e-mail: tso@med.tohoku.ac.jp