Altered B Cell Metabolic Pathways Characterize Type 1 Diabetes Progression

Abstract

Type 1 diabetes (T1D) results in immune-mediated destruction of insulin-producing beta cells in the pancreas. B cells have been identified as critical, pathogenic antigen presenting cells and their specificity drives disease progression. At the same time, immunosuppressive, IL-10- producing regulatory B cells (Bregs) have been shown to play protective roles in mouse models of several autoimmune diseases, including rheumatoid arthritis and multiple sclerosis. In these models, microenvironmental stimuli induce regulatory B cell differentiation. Specifically, signaling through hypoxia-inducible factor 1 (HIF-1) drives a glycolytic flux that facilitates Breg expansion. While Breg frequencies are decreased in individuals with T1D compared to healthy controls, the role B regs play, how microenvironmental stimuli influence their differentiation, and whether this is altered in T1D progression, which is characterized by progressive, systemic hyperglycemia, are less clear. Here we examine the relationship between B cell differentiation, cellular metabolism, and HIF-1 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 skew the B cell repertoire toward inflammatory, rather than regulatory B cell subsets to drive T1D development. Consequently, HIF-1 activation to expand regulatory B cell populations may be a viable option for immune modulation.