Altered B Cell Metabolic Pathways Characterize Type 1 Diabetes Progression

Abstract

SUMMARYType 1 diabetes (T1D) results in immune-mediated destruction of insulin-producing beta cells I the pancreas. B cells have been identified as critical antigen presenting cells and their specificity drives disease progression. More recently, they have also been shown to have the capacity to develop into suppressive, regulatory B cells that ameliorate autoimmune disease in animal models of rheumatoid arthritis and multiple sclerosis. In these models, signaling through hypoxia-inducible factor 1α (HIF-1α) drives a glycolytic flux that facilitates expansion of regulatory B cells. Here we examine the relationship between B cell development, cellular metabolism, and HIF-1α to reveal that in a mouse model of autoimmune diabetes, B cells have distinct metabolic characteristics that change with disease progression. Further, response to hypoxia in autoimmune B cells is distinct from the response by non-autoimmune control B cells. Together, these data suggest that dysregulated HIF signaling may drive T1D progression and activation of HIF-1α to expand regulatory B cell populations may be a viable option for immune modulation.