Abstract
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 TCRbeta-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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Autoantigens / immunology
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Autoantigens / metabolism
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / pathology*
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Cell Death / immunology
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Cell Movement / immunology
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Diabetes Mellitus, Type 1 / immunology
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Diabetes Mellitus, Type 1 / pathology
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Diabetes Mellitus, Type 1 / prevention & control*
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Disease Progression
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Epitopes, T-Lymphocyte / immunology
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Female
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Glucose-6-Phosphatase / administration & dosage
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Glucose-6-Phosphatase / biosynthesis
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Glucose-6-Phosphatase / immunology
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H-2 Antigens / administration & dosage*
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H-2 Antigens / toxicity
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Histocompatibility Antigen H-2D
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Immunotoxins / administration & dosage*
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Immunotoxins / toxicity
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Islets of Langerhans / immunology
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Islets of Langerhans / pathology
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Mice
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Mice, Inbred NOD
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Mice, SCID
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Mice, Transgenic
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Molecular Mimicry / immunology
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Proteins / administration & dosage
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Proteins / immunology
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Receptors, Antigen, T-Cell, alpha-beta / biosynthesis
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Receptors, Antigen, T-Cell, alpha-beta / genetics
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Ribosome Inactivating Proteins, Type 1 / administration & dosage
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Ribosome Inactivating Proteins, Type 1 / toxicity*
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Saporins
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beta 2-Microglobulin / administration & dosage*
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beta 2-Microglobulin / toxicity
Substances
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Autoantigens
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Epitopes, T-Lymphocyte
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H-2 Antigens
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H-2K(K) antigen
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Histocompatibility Antigen H-2D
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Immunotoxins
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Proteins
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Receptors, Antigen, T-Cell, alpha-beta
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Ribosome Inactivating Proteins, Type 1
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beta 2-Microglobulin
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Glucose-6-Phosphatase
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G6pc2 protein, mouse
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Saporins