Essential role of the transcription factor Bhlhe41 in regulating the development, self-renewal and BCR repertoire of B-1a cells

Innate-like B-1a cells provide a first line of defense against pathogens, yet little is known about their transcriptional control. Here we identified an essential role of the transcription factor Bhlhe41, with a lesser contribution of Bhlhe40, in controlling late stages of B-1a cell differentiation. Bhlhe41(–/–)Bhlhe40(–/–) B-1a cells were severely reduced as compared to their wild-type counterparts. Mutant B-1a cells exhibited an abnormal cell-surface phenotype and altered B-cell receptor (BCR) repertoire exemplified by loss of the phosphatidylcholine-specific V(H)12/Vκ4 BCR. Expression of a pre-rearranged V(H)12/Vκ4 BCR failed to rescue the mutant phenotype and revealed enhanced proliferation accompanied with increased cell death. Bhlhe41 directly repressed the expression of cell cycle regulators and inhibitors of BCR signaling, while enabling pro-survival cytokine signaling. Thus, Bhlhe41 controls the development, BCR repertoire and self-renewal of B-1a cells.