Bim is a candidate gene in the regulation of merocytic dendritic cell proportion

Abstract

Abstract In contrast to conventional dendritic cells (cDC), when merocytic DC (mcDC) present antigens (Ag) derived from apoptotic bodies, T cell anergy is reversed rather than induced. Although helpful to tumour clearance, reversing T cell anergy is detrimental in autoimmunity. Interestingly, mcDC are present in higher proportion in type 1 diabetes (T1D)-prone NOD mice than in B6 mice. Recently, we found that the Idd13 T1D locus is linked to the control of mcDC number. Indeed, NOD.B6-Idd13 congenic mice are resistant to T1D and have the same low number of mcDC as the parental B6 mice. Thus, we hypothesize that defining the genetic factor implicated in the regulation of mcDC number could help maintain self-tolerance and prevent T1D onset. Within the Idd13 locus, both B2m and Bim are likely candidate genes. By exploiting both B2m−/−and Bim−/−mice, we show that B2m does not affect mcDC number while mcDC were significantly increased in Bim−/−mice. Competitive hematopoietic chimera validate Bim as an intrinsic factor implicated in the regulation of mcDC proportion. In line with a role for Bim in regulating mcDC number, we demonstrate that the caspase activity and Bcl2 expression is not differentially expressed between the different mouse model, suggesting that Bim is implicated in mcDC proportion regulation via a caspase-independent pathway. Together, these data demonstrate that Bim, encoded within the Idd13 locus on the chromosome 2 modulates the number of mcDC. Identifying factors that facilitate apoptosis of mcDC may help prevent autoimmunity. Still, whether restoring Bim expression in NOD mice would prevent T1D remains to be addressed.