Abstract
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 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 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.