The transcription factor Zeb2 drives differentiation of age-associated B cells

Age-associated B cells (ABCs) accumulate after infection, during aging, and in systemic autoimmunity, contributing to pathogenesis in the latter[1][1]. To date, their precise ontogeny and whether they represent a B cell subset distinct from the other major effector subsets - plasma cells and memory B cells - remain unknown. We asked whether ABC formation requires the expression of a unique transcription factor. Here, we used single-cell RNA sequencing to identify differentially-expressed transcription factors shared by ABCs from both lupus patient and lupus-prone mice. Using an arrayed CRISPR screen, we show Zeb2 is essential for ABC differentiation in vitro. Selective deficiency of Zeb2 in B cells also leads to impaired ABC formation in vivo. Zeb2 drove ABC specification by directly binding the promoters of ABC signature genes including Itgax and Itgam encoding for CD11c and CD11b respectively. Zeb2 also targeted molecules involved in cytokine receptor signaling via the JAK/STAT pathway including Il21r and Socs5 . Administration of the approved JAK/STAT inhibitor tofacitinib effectively ameliorated ABC accumulation in mice and patients with autoimmunity. This study reveals ABCs represent a distinct B cell subset dependent on Zeb2 expression, and provides a rationale for the use of JAK/STAT inhibitors to treat ABC-mediated autoimmune diseases. ### Competing Interest Statement The authors have declared no competing interest. [1]: #ref-1