Characterization of Diabetogenic CD8+ T Cells: IMMUNE THERAPY WITH METABOLIC BLOCKADE

J Biol Chem. 2016 May 20;291(21):11230-40. doi: 10.1074/jbc.M115.713362. Epub 2016 Mar 18.


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.

Keywords: T-cell; autoimmunity; beta cell (B-cell); immunology; type 1 diabetes.

Publication types

  • Research Support, N.I.H., Extramural
  • Comment

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology*
  • Diabetes Mellitus, Type 1 / genetics*
  • Insulin
  • Islets of Langerhans / immunology
  • Mice, Inbred NOD
  • Mice, Transgenic
  • Prediabetic State / immunology


  • Insulin