Abstract
Nonobese diabetic (NOD) mice carrying a transgenic TCR from an islet Ag-specific CD4 T cell clone, BDC2.5, do not develop diabetes. In contrast, the same transgenic NOD mice on the SCID background develop diabetes within 4 wk after birth. Using a newly developed mAb specific for the BDC2.5 TCR, we examined the interaction between diabetogenic T cells and regulatory T cells in NOD.BDC transgenic mice. CD4 T cells from NOD.BDC mice, expressing high levels of the clonotype, transfer diabetes to NOD.SCID recipients. In contrast, CD4 T cells expressing low levels due to the expression of both transgenic and endogenous TCR alpha-chains inhibit diabetes transfer. The clonotype-low CD4 T cells appear late in the ontogeny in the thymus and peripheral lymphoid organs, coinciding with resistance to cyclophosphamide-induced diabetes. These results demonstrate that diabetic processes in NOD.BDC mice are regulated by a balance between diabetogenic T cells and regulatory T cells. In the absence of specific manipulation, regulatory T cell function seems to be dominant and mice remain diabetes free. Understanding of mechanisms by which regulatory T cells inhibit diabetogenic processes would provide means to prevent diabetes development in high-risk human populations.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adoptive Transfer
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Aging / genetics
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Aging / immunology
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Animals
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Antibodies, Monoclonal / biosynthesis
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Antibody Specificity / genetics
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Autoantibodies / biosynthesis
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Autoantibodies / metabolism
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Autoantigens / immunology*
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Autoantigens / metabolism
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CD4-Positive T-Lymphocytes / cytology
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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CD4-Positive T-Lymphocytes / transplantation
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Cell Differentiation / immunology
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Cyclophosphamide / administration & dosage
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Diabetes Mellitus, Type 1 / chemically induced
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Diabetes Mellitus, Type 1 / etiology
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Diabetes Mellitus, Type 1 / immunology*
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Epitopes, T-Lymphocyte / immunology*
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Immunophenotyping
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Injections, Intraperitoneal
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Islets of Langerhans / immunology*
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Mice
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Mice, Inbred BALB C
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Mice, Inbred NOD
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Mice, SCID
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Mice, Transgenic
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Receptors, Antigen, T-Cell / genetics*
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Receptors, Antigen, T-Cell / immunology*
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Spleen / cytology
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Spleen / transplantation
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T-Lymphocyte Subsets / cytology
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T-Lymphocyte Subsets / immunology*
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T-Lymphocyte Subsets / metabolism*
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T-Lymphocyte Subsets / transplantation
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Thymus Gland / cytology
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Thymus Gland / immunology
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Thymus Gland / metabolism
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Transgenes / immunology
Substances
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Antibodies, Monoclonal
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Autoantibodies
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Autoantigens
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Epitopes, T-Lymphocyte
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Receptors, Antigen, T-Cell
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Cyclophosphamide