TCF1 and LEF1 promote B-1a cell homeostasis and regulatory function.
Shen Q., Wang H., Roco JA., Meng X., Bosticardo M., Hodges M., Battaglia M., Feng Z-P., Talks BJ., Powell J., Shanmugiah VBM., Chu J., Rahman NM., Elsheikh A., Chakravarty P., Grenov A., Emmerich M., Delmonte OM., Freeman AF., Keller MD., Belaid B., Papa I., Lee JC., Cañete PF., Gonzalez-Figueroa P., Zhang Y., Xue H-H., Turajlic S., Notarangelo LD., Haniffa M., Garrett-Sinha LA., Parry HM., Kanellakis NI., Vinuesa CG.
B-1 cells are innate-like immune cells abundant in serosal cavities with antibodies enriched in bacterial recognition, yet their existence in humans has been controversial1-3. The CD5+ B-1a subset expresses anti-inflammatory molecules including IL-10, PDL1 and CTLA4 and can be immunoregulatory4-6. Unlike conventional B cells that are continuously replenished, B-1a cells are produced early in life and maintained through self-renewal7. Here we show that the transcription factors TCF1 and LEF1 are critical regulators of B-1a cells. LEF1 expression is highest in fetal and bone marrow B-1 progenitors, whereas the levels of TCF1 are higher in splenic and peritoneal B-1 cells than in B-1 progenitors. TCF1-LEF1 double deficient mice have reduced B-1a cells and defective B-1a cell maintenance. These transcription factors promote MYC-dependent metabolic pathways and induce a stem-like population upon activation, partly via IL-10 production. In the absence of TCF1 and LEF1, B-1 cells proliferate excessively and acquire an exhausted phenotype with reduced IL-10 and PDL1 expression. Furthermore, adoptive transfer of B-1 cells lacking TCF1 and LEF1 fails to suppress brain inflammation. These transcription factors are also expressed in human chronic lymphocytic leukaemia B cells and in a B-1-like population that is abundant in pleural fluid and circulation of some patients with pleural infection. Our findings define a TCF1-LEF1-driven transcriptional program that integrates stemness and regulatory function in B-1a cells.