Accelerated plasma cell differentiation in Bach2-deficiency is caused by altered IRF4 function. Mus musculus strain:C57BL/6J

Transcription factors BACH2 and IRF4 are both essential for class switch recombination (CSR) occurring in activated B cell, while they oppositely regulate plasma cell (PC) differentiation. Here, we investigated how the roles of BACH2 and IRF4 are integrated along CSR and PC differentiation. We found that BACH2 organized heterochromatin formation of target gene loci including IRF4-activation targets such as Aicda, an inducer of CSR, and Prdm1, a master regulator of PC. These gene loci were released from heterochromatin in response to B-cell receptor stimulation, coupled to the AKT-mTOR pathway. In Bach2-deficient B cells, PC genes were activated by the accumulated IRF4, without an increase in Irf4 mRNA. The mechanism involved the reduced function of PU.1-IRF4 heterodimer, which promotes BACH2 function by inducing the expression of Bach2 and Pten, a negative regulator of AKT signaling. Importantly, AKT activity was elevated in Bach2-deficient B cells, resulting in IRF4 protein accumulation. Thus, BACH2 and IRF4 mutually modulate each function, and BACH2 inhibits PC differentiation by both the repression of PC genes and the restriction of IRF4 protein accumulation.