The transcription factors TCF1 and LEF1 drive B-1a cell development, self-renewal, and regulatory function.

B-1 cells are abundant in peritoneal and pleural cavities and produce natural and microbial-induced IgM and IgA1–4.CD5+ B-1 cells known as “B-1a” represent the largest source of B cell-derived IL-105,6, an important regulator of inflammation and autoimmunity7. Unlike conventional B cells that are produced daily in the bone marrow, B-1a cells are predominantly generated from foetal precursors and maintained by self-renewal8 but the molecular mechanisms that underpin this stem cell-like property and their regulatory potential are poorly understood. Here we show that both mouse and human B-1a cells express high amounts of TCF1 and LEF1 and these transcription factors drive their formation and self-renewal promoting oxidative and fatty acid metabolism. Deficiency of TCF1/LEF1 in B-1a cells leads to downregulation of Ets1 and Myc targets, and severely compromises their maintenance over time. TCF1 and LEF1 are also essential for IL-10 and PD-L1 expression upon B-1 cell activation and repression of CNS inflammation. TCF1/LEF1 mediate the emergence of a mixed cell progeny at the third B-1 cell division including a stem-cell-like population. B-1 cells lacking TCF1/LEF1 continue proliferating and acquire an exhausted phenotype reminiscent of age-associated B cells. These findings identify a transcriptional program that links stemness with regulatory potential in B-1a cells.