Abstract
Type 1 diabetes mellitus is caused by the killing of insulin-producing β cells by CD8+T cells. The disease progression, which is chronic, does not follow a course like responses to conventional antigens such as viruses, but accelerates as glucose tolerance deteriorates. To identify the unique features of the autoimmune effectors that may explain this behavior, we analyzed diabetogenic CD8+ T cells that recognize a peptide from the diabetes antigen IGRP (NRP-V7-reactive) in prediabetic NOD mice and compared them to others that shared their phenotype (CD44(+)CD62L(lo)PD-1(+)CXCR3(+)) but negative for diabetes antigen tetramers and to LCMV (lymphocytic choriomeningitis)-reactive CD8+ T cells. 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 β cells. We compared gene expression in the three groups of cells compared with the other two subsets of cells, and 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 2-deoxyglucose to block aerobic glycolysis, there was a reduction in the diabetes antigen versus other cells of similar phenotype and loss of lymphoid cells infiltrating the islets. In addition, treatment of NOD mice with 2-deoxyglucose resulted in improved β cell granularity. These findings identify a link between metabolic disturbances and autoreactive T cells that promotes development of autoimmune diabetes.
Highlights
Type 1 diabetes (T1D)2 in humans is an autoimmune disease involving the destruction of insulin-producing  cells in the islets of Langerhans by CD8ϩ T cells [1,2,3,4,5,6]
We found that compared with CD8ϩ T cells that share the phenotype but not the antigen specificity of the IGRP-reactive T cells as well as viral antigenreactive CD8ϩ T cells, the expansion and effector function of the NRP-V7-reactive T cells are dependent on glucose availability
These findings suggest that diabetogenic CD8 T cells are present before 10 weeks of age, but there is a dramatic increase in the frequency of the cells that closely aligns with the beginning of impaired glucose tolerance [24]
Summary
These data showed that  cell killing is significantly greater when glucose intolerance is present These observations led us to consider whether there were interactions between the pathogenic immune cells and host factors that may affect the progression of disease. To understand these interactions, we focused our studies on CD8ϩ T cells that are reactive to an epitope of glucose-6-phosphatase catalytic subunit related protein (IGRP) and are known to cause  cell killing. IGRP-reactive CD8ϩ T cells can be found in NOD mice by staining with MHC-I tetramer loaded with NRP-V7 peptide [5, 12, 16] They can cause diabetes when they receive help from CD4ϩ T cells [13]. Our work suggests that elevated glucose may drive a feed-forward mechanism in which modest hyperglycemia provides fuel to effector T cells and leads to the maintenance of pathogenic T cells and accelerated  cell destruction
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