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. We show here that TRAF3 deficiency led to impaired Akt activation and thus to impaired in vitro skewing of CD4 T cells into the T_H1 and T_H2 fates. We investigated the role of TRAF3 in regulation of signaling pathways that drive T_H1 and T_H2 differentiation and found that TRAF3 enhanced activation of signal transducer and activator of transcription 6 (STAT6), thus promoting skewing toward the T_H2 fate. TRAF3 promoted STAT6 activation by regulating recruitment of the inhibitory molecule protein tyrosine phosphatase 1B 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.