Lymphocyte metabolism in the islet microenvironment

Abstract

Abstract Type 1 diabetes (T1D) results in immune-mediated destruction of insulin-producing beta cells in the pancreas. Immune intervention to prevent or reverse T1D is an appealing therapeutic approach; however, selective targeting of autoreactive lymphocytes remains an elusive goal. Recently, cellular metabolism has emerged as a potent modulator of immune cell function. The metabolic state of lymphocytic infiltrate within the highly vascularized islet, termed insulitis, is not known. To test the hypothesis that pathogenic, islet-infiltrating lymphocytes have a distinct metabolic phenotype that has the potential to be selectively targeted, we compared the metabolic signatures of islet infiltrating lymphocytes in two transgenic mouse models. VH125SD.NOD mice develop accelerated diabetes and robust insulitis. BDC2.5.NOD develop insulitis but are protected from T1D. These models were used as examples of pathogenic and protective insulitis, respectively. Mitochondrial polarity was significantly increased in VH125SD.NOD islet-infiltrating B cells compared to BDC2.5.NOD islet-infiltrating B cells. Mitochondrial polarity was also increased in insulin-binding B cells compared to non-insulin-binding B cells in the pancreas, but not in the spleen or pancreatic lymph nodes. Assessment of hypoxia in islet-infiltrating lymphocytes revealed that the oxygen-sensing transcription factor, hypoxia-inducible factor 1α was increased in islet-infiltrating B cells specifically. Together, these findings suggest that tissue specific changes drive metabolic reprogramming at the site of autoimmune attack in the islet and that these metabolic pathways have the potential to be targeted for selective therapeutic interventions in T1D.