Schnurri 3 promotes Th2 cytokine production during the late phase of T‐cell antigen stimulation

Th1 and Th2 polarization is determined by the coordination of numerous factors including the affinity and strength of the antigen‐receptor interaction, predominant cytokine environment, and costimulatory molecules present. Here, we show that Schnurri (SHN) proteins have distinct roles in Th1 and Th2 polarization. SHN2 was previously found to block the induction of GATA3 and Th2 differentiation. We found that, in contrast to SHN2, SHN3 is critical for IL‐4 production and Th2 polarization. Strength of stimulation controls SHN2 and SHN3 expression patterns, where higher doses of antigen receptor stimulation promoted SHN3 expression and IL‐4 production, along with repression of SHN2 expression. SHN3‐deficient T cells showed a substantial defect in IL‐4 production and expression of AP‐1 components, particularly c‐Jun and Jun B. This loss of early IL‐4 production led to reduced GATA3 expression and impaired Th2 differentiation. Together, these findings uncover SHN3 as a novel, critical regulator of Th2 development. Earlier studies showed that antigen receptor signal strength can dictate Th1/Th2 polarization. Prolonged antigen receptor signaling induces the expression of a transcription factor, SHN‐3, which is required for initial Th2‐cell differentiation. Loss of SHN‐3 expression causes a reduction in IL‐4 production and causes Th1‐dominant in vivo immune responses.