IFNγ induces epigenetic programming of human T-bethi B cells and promotes TLR7/8 and IL-21 induced differentiation

Abstract

Although B cells expressing the IFN{gamma}R or the IFN{gamma}-inducible transcription factor T-bet drive 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 IgDnegCD27negCD11c+CXCR5neg (DN2) pre-antibody secreting cell (pre-ASC) subset. We demonstrate that naive B cells form T-bethi 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.