Abstract
Activation-induced cell death (AICD) plays a key role in the homeostasis of the immune system. Autoreactive T cells are eliminated through AICD both from the thymus and periphery. In this study, we show that NOD peripheral T cells, especially CD8(+) T cells, display a decreased susceptibility to anti-CD3-induced AICD in vivo compared with T cells from diabetes-resistant B6, nonobese diabetes-resistant, and NOD.B6Idd4 mice. The susceptibility of NOD CD8(+) T cells to AICD varies in an age- and dose-dependent manner upon stimulation in vivo with either a mitogenic or nonmitogenic anti-CD3. NOD T cells preactivated by anti-CD3 in vivo are less susceptible than B6 T cells to TCR-induced AICD. Treatment of NOD mice with a mitogenic anti-CD3 depletes CD4(+)CD25(-)CD62L(+) but not CD4(+)CD25(+)CD62L(+) T cells, thereby resulting in an increase of the latter subset in the spleen. Treatment with a nonmitogenic anti-CD3 mAb delays the onset of T1D in 8.3 TCR transgenic NOD mice. These results demonstrate that the capacity of anti-CD3 to protect NOD mice from T1D correlates with its ability to perturb T cell homeostasis by inducing CD8(+) T cell AICD and increasing the number of CD4(+)CD25(+)CD62L(+) T cells in the periphery.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Aging / genetics
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Aging / immunology
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Animals
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Antibodies, Monoclonal / pharmacology*
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Antibodies, Monoclonal / therapeutic use
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Apoptosis / genetics
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Apoptosis / immunology*
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CD3 Complex / immunology*
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / pathology
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / pathology
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Cell Death / genetics
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Cell Death / immunology
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Diabetes Mellitus, Type 1 / genetics
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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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Female
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Genetic Predisposition to Disease
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Homeostasis / genetics
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Homeostasis / immunology*
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Humans
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Interferon-gamma / antagonists & inhibitors
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Interferon-gamma / metabolism
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Interleukin-10 / antagonists & inhibitors
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Interleukin-10 / metabolism
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Interleukin-4 / antagonists & inhibitors
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Interleukin-4 / metabolism
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L-Selectin / biosynthesis
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Lymphocyte Activation / genetics
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Lymphocyte Depletion
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Inbred NOD
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Mice, Transgenic
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Prediabetic State / genetics
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Prediabetic State / immunology*
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Prediabetic State / pathology
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Prediabetic State / prevention & control
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Receptors, Antigen, T-Cell, alpha-beta / genetics
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Receptors, Interleukin-2 / biosynthesis
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Spleen / cytology
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Spleen / immunology
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T-Lymphocyte Subsets / immunology*
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T-Lymphocyte Subsets / metabolism
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T-Lymphocyte Subsets / pathology
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Transforming Growth Factor beta / antagonists & inhibitors
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Transforming Growth Factor beta / metabolism
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Antibodies, Monoclonal
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CD3 Complex
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Receptors, Antigen, T-Cell, alpha-beta
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Receptors, Interleukin-2
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Transforming Growth Factor beta
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Tumor Necrosis Factor-alpha
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L-Selectin
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Interleukin-10
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Interleukin-4
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Interferon-gamma