Comparison of gene expression by microarray in diabetes antigen specific (NRP-V7), LCMV antigen specific (GP33), and CD8+ T cells of similar phenotype from NOD mice. Mus sp.

Type 1 diabetes mellitus (T1D) is caused by killing of insulin producing β cells by CD8+T cells. The disease progression accelerates as glucose tolerance deteriorates suggesting that acquired factors contribute. To identify how environmental factors may lead to the expansion and pathogenicity of the diabetogenic T cells, we analyzed diabetogenic NRP-V7-reactive CD8+ T cells that recognize a peptide from the diabetes antigen IGRP in prediabetic NOD mice. There was an increase in the frequency of the NRP-V7-reactive cells coinciding with the time of glucose intolerance. The T cells persisted in hyperglycemic NOD mice maintained with an insulin pellet despite destruction of beta cells. We compared gene expression in the NRP-V7-reactive T cells to others that shared their phenotype but not selected for reactivity to diabetes antigens viral antigen reactive cells. Compared to these other cells, the NRP-V7-reactive cells exhibited gene expression of memory precursor effector cells. They had reduced cellular proliferation and were less dependent on oxidative phosphorylation. When prediabetic NOD mice were treated with 2DG to block aerobic glycolysis, there was a reduction in the diabetes antigen vs other cells of similar phenotype and loss of lymphoid cells infiltrating the islets. In addition, treatment of NOD mice with 2DG resulted in improved cell granularity. These findings identify a link between metabolic disturbances and autoreactive T cells that promotes development of autoimmune diabetes. Overall design: To distinguish the features of the autoreactive, viral antigen reactive CD8+ T cells from other cells in NOD mice that share the phenotype of these cells, we sorted CD8+ T cells that showed high expression of CD44, PD-1, CXCR3, and low expression of CD62L, and compared gene expression by microarray to the gp33 and NRP-V7 tetramer+ CD8+ T cells, sorted from the spleens mesenteric and pancreatic lymph nodes.