期刊
JOURNAL OF IMMUNOLOGY
卷 184, 期 8, 页码 4196-4204出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.0903931
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资金
- Juvenile Diabetes Research Foundation [1-2008-24]
- National Institutes of Health [A1052435]
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health [K08-DK082264]
There is compelling evidence that self-reactive CD8(+) T cells are a major factor in development and progression of type 1 diabetes in animals and humans. Hence, great effort has been expended to define the specificity of autoimmune CD8+ T cells and to alter their responses. Much work has focused on tolerization of T cells using proteins or peptides. A weakness in this approach is that residual autoreactive T cells may be activated and exacerbate disease. In this report, we use a novel approach, toxin-coupled MHC class I tetramers. Used for some time to identify Ag-specific cells, in this study, we use that same property to delete the Ag-specific cells. We show that saporin-coupled tetramers can delete islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)-reactive T cells in vitro and in vivo. Sequence analysis of TCR beta-chains of IGRP(+) cells reveals the repertoire complexity in the islets is markedly decreased as NOD mice age and significantly altered in toxic tetramer-treated NOD mice. Further tetramer T cells in the islets are almost completely deleted, and, surprisingly, loss of tetramer T cells in the islets is long lasting. Finally, we show deletion at 8 wk of age of IGRP(+) CD8(+) T cells, but not dystophia myotonica kinase- or insulin B-reactive cells, significantly delays diabetes in NOD mice. The Journal of Immunology, 2010, 184: 4196-4204.
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