T-bet Transcription Factor Promotes Antibody-Secreting Cell Differentiation by Limiting the Inflammatory Effects of IFN-γ on B Cells

Although viral infections elicit robust interferon-γ (IFN-γ) and long-lived antibody-secreting cell (ASC) responses, the roles for IFN-γ and IFN-γ-induced transcription factors (TFs) in ASC development are unclear. We showed that B cell intrinsic expression of IFN-γR and the IFN-γ-induced TF T-bet were required for T-helper 1 cell-induced differentiation of B cells into ASCs. IFN-γR signaling induced Blimp1 expression in B cells but also initiated an inflammatory gene program that, if not restrained, prevented ASC formation. T-bet did not affect Blimp1 upregulation in IFN-γ-activated B cells but instead regulated chromatin accessibility within the Ifng and Ifngr2 loci and repressed the IFN-γ-induced inflammatory gene program. Consistent with this, B cell intrinsic T-bet was required for formation of long-lived ASCs and secondary ASCs following viral, but not nematode, infection. Therefore, T-bet facilitates differentiation of IFN-γ-activated inflammatory effector B cells into ASCs in the setting of IFN-γ-, but not IL-4-, induced inflammatory responses. •Differentiation of Th1-activated B (Be1) cells requires B intrinsic T-bet and IFN-γR•Be1 differentiation requires T-bet repression of NF-κB, TLR, and STAT pathways•Plasma cell formation in Be2 cultures and nematode infection is T-bet independent•T-bet controls formation of long-lived and secondary plasma cells in flu infection T-bet-expressing B cells are expanded in autoimmunity and viral infection; however, whether these cells represent early plasma cells was unknown. Stone et al. identify T-bet-repressed pathways that permit plasma cell differentiation in the presence of IFN-γ. They show that T-bet-expressing B cells are required for long-lived immunity to flu.