TRAF3 regulates STAT6 activation and T-helper cell differentiation by modulating the phosphatase PTP1B.

The adaptor protein tumor necrosis factor receptor-associated factor 3 (TRAF3) is a multifaceted regulator of lymphocyte biology that plays key roles in modulation of the molecular signals required for T-cell activation and function. TRAF3 regulates signals mediated by the T-cell receptor (TCR), costimulatory molecules, and cytokine receptors, which each drive activation of the serine/threonine kinase Akt. The impact of TRAF3 upon TCR-CD28-mediated activation of Akt, and thus on the diverse cellular processes regulated by Akt, including CD4 T-cell fate decisions, remains poorly understood.

Multiple mechanisms for TRAF3-mediated regulation of the T cell costimulatory receptor GITR.

Tumor necrosis factor receptor (TNFR)-associated factor 3 (TRAF3) plays context-specific roles in multiple receptor-mediated signaling pathways in different cell types. Mice lacking TRAF3 in T cells display defective T-cell-mediated immune responses to immunization and infection and demonstrate defective early signaling via the TCR complex. However, the role of TRAF3 in the function of GITR/TNFRSF18, an important costimulatory member of the TNFR superfamily, is unclear.

TRAF3 in T Cells Restrains Negative Regulators of LAT to Promote TCR/CD28 Signaling.

The adaptor protein TNFR-associated factor 3 (TRAF3) is required for in vivo T cell effector functions and for normal TCR/CD28 signaling. TRAF3-mediated enhancement of TCR function requires engagement of both CD3 and CD28, but the molecular mechanisms underlying how TRAF3 interacts with and impacts TCR/CD28-mediated complexes to enhance their signaling remains an important knowledge gap. We investigated how TRAF3 is recruited to, and regulates, CD28 as a TCR costimulator.

Frontline Science: CD40 signaling restricts RNA virus replication in Mϕs, leading to rapid innate immune control of acute virus infection.

Many acute viral infections target tissue Mϕs, yet the mechanisms of Mϕ-mediated control of viruses are poorly understood. Here, we report that CD40 expressed by peritoneal Mϕs restricts early infection of a broad range of RNA viruses. Loss of CD40 expression enhanced virus replication as early as 12-24 h of infection and, conversely, stimulation of CD40 signaling with an agonistic Ab blocked infection.

TRAF family molecules in T cells: Multiple receptors and functions.

The TNFR superfamily of receptors, the major focus of the recent TNFR Superfamily Conference held in June 2019, employ the TNFR-associated factor (TRAF) family of adaptor proteins in key aspects of their signaling pathways. Although many early studies investigated TRAF functions via exogenous overexpression in nonhematopoietic cell lines, it has subsequently become clear that whereas TRAFs share some overlap in function, each also plays unique biologic roles, that can be highly context dependent. This brief review summarizes the current state of knowledge of functions of each of the TRAF molecules that mediate important functions in T lymphocytes: TRAFs 1, 2, 3, 5, and 6.