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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

ABSTRACT: 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.

ORGANISM(S): Mus musculus Mus sp.

PROVIDER: GSE79200 | GEO | 2016/03/17

SECONDARY ACCESSION(S): PRJNA315140

REPOSITORIES: GEO

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Project description:Type 1 diabetes is a multigenic disease caused by T-cell mediated destruction of the insulin producing β-cells. Although conventional (targeted) approaches of identifying causative genes have advanced our knowledge of this disease, many questions remain unanswered. Using a whole molecular systems study, we unraveled the genes/molecular pathways that are altered in CD4 T-cells from young NOD mice prior to insulitis (lymphocytic infiltration into the pancreas). Many of the CD4 T-cell altered genes lie within known diabetes susceptibility regions (Idd), including several genes in the diabetes resistance region Idd13 and two genes (Khdrbs1 and Ptp4a2) in the CD4 T-cell diabetogenic activity region Idd9/11. Alterations involved apoptosis/cell proliferation and metabolic pathways (predominant at 2 weeks), inflammation and cell signaling/activation (predominant at 3 weeks), and innate and adaptive immune responses (predominant at 4 weeks). We identified several factors that may regulate these abnormalities: IRF-1, HNF4A, TP53, BCL2L1 (lies within Idd13), IFNG, IL4, IL15, and prostaglandin E2, which were common to all 3 ages; AR and IL6 to 2 and 4 weeks; and Interferon (IFN-I) and IRF-7 to 3 and 4 weeks. Others were unique to the various ages (e. g. MYC, JUN, and APP to 2 weeks; TNF, TGFB1, NFKB, ERK, and p38MAPK to 3 weeks; and IL12 and STAT4 to 4 weeks). Our data suggest that diabetes resistance genes in Idd13 and Idd9/11, and BCL2L1, IL6-AR and IFNG-IRF-1-IFN-I/IRF-7-IL12 pathways play an important role in CD4 T-cells in the early pathogenesis of autoimmune diabetes. Thus, the alternative approach of investigation at the molecular systems level has captured new information, which combined with validation studies, offers the opportunity to test hypotheses on the role played by the genes/molecular pathways identified in this study, to understand better the mechanisms of autoimmune diabetes in CD4 T-cells, and to develop new therapeutic strategies for the disease. CD4 T-cells were purified from spleen leukocytes collected from 2-, 3- and 4-week old NOD mice and two age-matched control strains, NOR, and C57BL/6, (n=5 for each strain and each age group; except NOD2wk). NOR is an insulitis- and diabetes-free control strain that shares shares ~88% of its genome with NOD mice, including the diabetogenic H2g7 MHC haplotype and several important non-MHC T1D susceptibility loci. C57BL/6 is also a diabetes-resitant strain, but it is more genetically distantly related to NOD.

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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

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