Type 1 diabetes (T1D) results in the immune-mediated destruction of insulin-producing beta cells in the pancreas. As such, immune intervention to prevent or delay T1D is an appealing therapeutic approach. Development of an antigen-specific intervention that targets the diabetogenic immune response without compromising systemic immunity is complicated by an expanding list of antigenic targets, including post-translationally modified peptides generated at the site of autoimmune attack in the islet. Thus, development of effective antigen-based therapy requires not only antigen identification, but also understanding of the unique antigen processing environment facilitated by the islet itself. Recently, cellular metabolism has emerged as a potent modulator of immune cell function. However, the metabolic state lymphocytic infiltrate in the islet, termed insulitis, is not known. Given the highly vascularized nature of the islet needed to accommodate the metabolic demand associated with insulin secretion, we sought to characterize the islet’s distinct metabolic environment and its influence on T-B cell interactions at the site of autoimmune attack. Using a transgenic mouse model that develops accelerated diabetes (VH125SD.NOD), we assessed the metabolic signature of islet-infiltrating lymphocytes compared to those in the spleen and pancreatic lymph nodes. We determined that islet-infiltrating lymphocytes are characterized by decreased glucose uptake in CD4 and CD8 T cell subsets. Mitochondrial mass and polarity were decreased in all subsets compared to secondary lymphoid organs, suggesting reduced metabolic fitness. These studies reveal a metabolic distinction between islet-infiltrating and secondary lymphoid organ lymphocytes and suggest that metabolic features that differentiate immune cells at the site of autoimmune attack are a potential target for selective therapeutic interventions in T1D.
J.L. Felton: None. R.H. Bonami: None. C. Hulbert: None. J.W. Thomas: None.