The transcription factor ZEB2 drives formation of age-associated B cells

Age-associated B cells (ABCs) accumulate during infection, aging and autoimmunity, contributing to lupus pathogenesis. Here, we screened for transcription factors driving ABC formation and found Zeb2 was required for human and mouse ABC differentiation in-vitro. ABCs were reduced in ZEB2 haploinsufficient individuals and in mice lacking Zeb2 in B cells. In mice with TLR7-driven lupus, Zeb2 was essential for ABC formation and autoimmune pathology. Zeb2 binds to the +20kb intronic enhancer of Mef2b, repressing Mef2b-mediated germinal center B cell differentiation and promoting ABC formation. Zeb2 also targets genes important for ABC specification and function including Itgax. Zeb2-driven ABC differentiation required Jak-Stat signaling, and treatment with the Jak1/3 inhibitor tofacitinib reduced ABC accumulation in mice and autoimmune patients. Zeb2 thus emerges as a driver of B-cell autoimmunity. 1. Examination of in vitro derived B cells in the presence of R848, CD40, anti-IgM or for R848, CD40, anti-IgM, IFNg, IL-21 3 days. 2. Examination of in vitro derived ABCs from Zeb2 deficient mice. 3. Examination of in vitro derived ABCs with Cas9-mediated ZEB2 or T-bet ablation. 4. Examination of in vitro derived ABCs with ZEB2 overexpression. 5. Examination of in vitro derived ABCs treated with tofacitinib.