The transcription factor Bcl11a is essential for functional B-1a cell maintenance during aging

B-1a cells, key natural IgM producers, are established during fetal and neonatal stages and maintained through self-renewal in adulthood. Essential for initial immune responses, these cells experience a functional decline and clonal expansion as they age, a process not yet fully understood. Our study identifies the transcription factor Bcl11a as crucial for maintaining B-1a cell numbers, showing variable expression between aged male and female mice. Enhanced Bcl11a expression in females correlates with increased B-1a cell counts, whereas its reduction in males leads to fewer cells. Deleting Bcl11a markedly reduces B-1a cell numbers across both sexes and all ages, highlighting its essential role in cell maintenance. Bcl11a's loss upregulates FcγRIV (Fcgr4), facilitating NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC). By repressing Fcgr4 directly and indirectly through Fcer1g, Bcl11a protects B-1a cells from ADCC, thus preserving their viability. This discovery emphasizes the potential of modulating Bcl11a expression to boost immune function in the elderly, underscoring its importance in immune surveillance and cellular integrity.