Characterization of Diabetogenic CD8+ T Cells
| Autor: | Steven H. Kleinstein, Justin Garyu, Jinxiu Rui, Matt M. Staron, Jared A. Shenson, Mohamed Uduman, Kevan C. Herold, Susan M. Kaech, Alex Stewart, Songyan Deng |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Type 1 diabetes medicine.medical_specialty Cell Biology Biology CXCR3 medicine.disease Biochemistry 03 medical and health sciences Interleukin 21 030104 developmental biology 0302 clinical medicine Endocrinology Antigen Internal medicine Immunology Interleukin 12 medicine Cytotoxic T cell Molecular Biology CD8 030215 immunology NOD mice |
| Zdroj: | Journal of Biological Chemistry. 291:11230-11240 |
| ISSN: | 0021-9258 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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