B cell-intrinsic MHCII expression restricts bacterial dissemination from the gut and maintains metabolic tone

Abstract

Abstract The expression of major histocompatibility complex class II (MHCII) molecules on the surface of B cells is essential for cognate interactions with T cells and ultimately the generation of high affinity serum antibody responses. Serum antibody responses play an important role in limiting the ability of gut microbes to colonize the systemic compartment. This is important because bacterial dissemination from the gut can have severe physiological consequences ranging from life-threatening septicemia to chronic low grade systemic inflammation. Here we use a conditional knockout mouse model (B-MHCII−/− mice) to determine the physiological implications of loss of T cell dependent serum antibody responses due to B cell-intrinsic ablation of MHCII expression. Loss of MHCII expression on B cells in B-MHCII−/− mice results in a significant reduction in the generation of long-lived plasma cells in the bone marrow and reduced circulating levels of IgG1. Reduced levels of circulating IgG1 is associated with increased levels of bacterial dissemination from the gut into the systemic compartment, as B-MHCII−/− mice have significantly increased titers of anaerobic bacterial colony-forming units in their livers. Importantly, increased bacterial dissemination is associated with an inability of B-MHCII−/− mice to gain weight, suggesting that bacterial dissemination in B-MHCII−/− mice drives the development of a metabolic disorder. Collectively, our data imply that beyond MHCII’s role in infectious immunity, MHCII-mediated antibody responses also play a fundamental role in establishing benign symbiosis with resident microbiota to maintain proper metabolic physiology.