IFN[gamma] induces epigenetic programming of human T-bet.sup.hi B cells and promotes TLR7/8 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.sup.negCD27.sup.negCD11c.sup.+CXCR5.sup.neg (DN2) pre-antibody secreting cell (pre-ASC) subset. We demonstrate that naïve B cells form T-bet.sup.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.