TRAF3 is critical for initial T follicular helper cell specification via coordination of the IL-6R/IL-2R-BCL6 signaling nexus

CD4+ T follicular helper (TFH) cells are essential for orchestrating robust humoral immunity, yet the signals that initiate TFH cell differentiation are not fully understood. We identified that the adapter protein TRAF3 was required for TFH cell differentiation and function during systemic inflammatory infections. Loss of CD4+ T cell-intrinsic TRAF3 impaired chromatin remodeling and transcriptional programming essential for TFH cell initiation and instead augmented TH1 development and function. TRAF3-deficient CD4+ T cells exhibited altered interleukin-6 (IL-6) and IL-2 responsiveness, which were coupled to failures in BCL6 expression. Enforced expression of either IL-6 receptor or BCL6 or blockade of IL-2 signaling was sufficient to rescue TFH cell differentiation. Human CD4+ T cells lacking TRAF3 exhibited impaired TFH polarization, supporting a conserved mechanism by which TRAF3 regulates CD4+ T cell fate determination. Thus, TRAF3 functions at the nexus of cytokine, transcriptional, and epigenetic nodes that promote the TFH cell specification during infection.