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 (T FH ) cells are essential for orchestrating robust humoral immunity, yet the signals that initiate T FH cell differentiation are not fully understood. We identified that the adapter protein TRAF3 was required for T FH cell differentiation and function during systemic inflammatory infections. Loss of CD4 + T cell–intrinsic TRAF3 impaired chromatin remodeling and transcriptional programming essential for T FH cell initiation and instead augmented T H 1 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 T FH cell differentiation. Human CD4 + T cells lacking TRAF3 exhibited impaired T FH 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 T FH cell specification during infection.