IFNγ induces epigenetic programming of human T-bet B cells and promotesTLR7/8 and IL-21 induced differentiation.

Although B cells expressing the IFN gamma R or the IFN gamma-inducible transcription factor T-bet promote autoimmunity in Systemic Lupus Erythematosus (SLE)-prone mouse models, the role for IFN gamma signaling in human antibody responses is unknown. We show that elevated levels of IFN gamma in SLE patients correlate with expansion of the T-bet expressing IgD(neg)CD27(neg)CD11c(+)CXCR5(neg)(DN2) pre-antibody secreting cell (pre-ASC) subset. We demonstrate that naive B cells form T-bet(hi) pre-ASCs following stimulation with either Th1 cells or with IFN gamma, IL-2, anti-Ig and TLR7/8 ligand and that IL-21 dependent ASC formation is significantly enhanced by IFN gamma or IFN gamma-producing T cells. IFN gamma promotes ASC development by synergizing with IL-2 and TLR7/8 ligands to induce genome-wide epigenetic reprogramming of B cells, which results in increased chromatin accessibility surrounding IRF4 and BLIMP1 binding motifs and epigenetic remodeling of IL21R and PRDM1 loci. Finally, we show that IFN gamma signals poise B cells to differentiate by increasing their responsiveness to IL-21.