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

The adaptor protein TNFR 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. We show here that TRAF3 deficiency led to impaired Akt activation, and thus to impaired in vitro skewing of CD4 T cells into the TH1 and TH2 fates. We investigated the role of TRAF3 in regulation of signaling pathways that drive TH1 and TH2 differentiation, and found that TRAF3 enhanced activation of Signal transducer and activator of transcription 6 (STAT6), thus promoting skewing toward the TH2 fate. TRAF3 promoted STAT6 activation by regulating recruitment of the inhibitory molecule Protein tyrosine phosphatase 1B (PTP1B) to the IL-4R signaling complex, in a manner that required integration of TCR/CD28- and IL-4R-mediated signals. This work reveals a new mechanism for TRAF3-mediated regulation of STAT6 activation in CD4 T cells, and adds to our understanding of the diverse roles played by TRAF3 as an important regulator of T cell biology.

TRAF3: Guardian of T lymphocyte functions.

Tumor necrosis factor receptor (TNFR)-associated factor 3 (TRAF3) is an adapter protein with many context-specific functions. Early studies of lymphocyte TRAF3 hinted at TRAF3's importance for T cell function, but elucidation of specific mechanisms was delayed by early lethality of globally TRAF3-/- mice. Development of a conditional TRAF3-deficient mouse enabled important descriptive and mechanistic insights into how TRAF3 promotes optimal T cell function. Signaling through the T cell antigen receptor (TCR) fails to induce normal proliferation and survival in TRAF3 -/- T cells, and TCR-activated cells in vitro and in vivo have deficient cytokine production. These defects can be traced to incorrect localization and function of negative regulatory phosphatases acting at different parts of the signaling cascade, as can dysregulated effector responses and memory T cell homeostasis in vivo and an enlarged regulatory T cell (Treg) compartment. The important regulatory activity of TRAF3 is also evident at members of the TNFR superfamily and cytokine receptors. Here, we review significant advances in mechanistic understanding of how TRAF3 regulates T cell differentiation and function, through modulation of signaling through the TCR, costimulatory receptors, and cytokine receptors. Finally, we briefly discuss the recent identification of families carrying single allele loss-of-function mutations in TRAF3, and compare the findings in their T cells with the T cell defects identified in mice whose T cells completely lack T cell TRAF3. Together, the body of work describing TRAF3-mediated regulation of T cell effector function and differentiation frame TRAF3 as an important modulator of T cell signal integration.

The Tumor Suppressor Protein TRAF3 Modulates GSK3 Activity and Susceptibility of B Lymphoma Cells to GSK3 Inhibition.

TNF receptor-associated factor 3 (TRAF3) is an adapter protein that inhibits many signals that promote B cell survival and activation. Mice with a B cell-specific TRAF3 deficiency and humans with a rare haploinsufficiency in TRAF3 have enhanced development of BCLs as they age. Loss-of-function mutations in TRAF3 are common in B cell malignancies. Recent studies show that pharmacological inhibition of the enzyme glycogen synthase kinase 3 (GSK3), which regulates cellular growth, survival, and metabolism, inhibits growth and survival of BCL-derived B cells. In this study, we found that TRAF3 and GSK3 associated in B cells. The relative levels of TRAF3 in BCL cell lines correlated positively with the ratio of inactive to total GSK3ß, and negatively correlated with susceptibility to GSK3 inhibition by the GSK3 inhibitory drug 9-ING-41, currently in clinical trials. Uniquely in BCLs with low TRAF3, GSK3 inhibition caused increased loss of the TRAF3-regulated, anti-apoptotic protein Mcl-1. GSK3 inhibition also blocked hyperresponsiveness to IL-6 receptor signaling in TRAF3-deficient BCL cells. Together, these results support the utility of 9-ING-41 as a treatment for BCL, and suggest that a decrease or loss of TRAF3 in BCLs could act as a biomarker for increased susceptibility to GSK3 inhibitor treatment.

TRAF3 enhances type I interferon receptor signaling in T cells by modulating the phosphatase PTPN22.

Type I interferons (IFNs) are among the most powerful tools that host cells deploy against intracellular pathogens. Their effectiveness is due both to the rapid, directly antiviral effects of IFN-stimulated gene products and to the effects of type I IFN on responding immune cells. Type I IFN signaling through its receptor, IFNAR, is tightly regulated at multiple steps in the signaling cascade, including at the level of IFNAR downstream effectors, which include the kinase JAK1 and the transcriptional regulator STAT1. Here, we found that tumor necrosis factor receptor (TNFR)-associated factor 3 (TRAF3) enhanced the activation of JAK1 and STAT1 specifically in CD4+ T cells by preventing recruitment of the negative regulatory phosphatase PTPN22 to the IFNAR complex. The balance between signals through IFNAR and other cytokine receptors influences CD4+ T cell differentiation and function during infections. Our work reveals TRAF3 and PTPN22 as key regulators of CD4+ T cell activation by type I IFNs.