Abstract
Anergic/suppressive CD4(+)CD25(+) T cells exist in animal models but their presence has not yet been demonstrated in humans. We have identified and characterized a human CD4(+)CD25(+) T cell subset, which constitutes 7-10 % of CD4(+) T cells in peripheral blood and tonsil. These cells are a CD45RO(+)CD45RB(low) highly differentiated primed T cell population that is anergic to stimulation. Depletion of this small subset from CD4(+) T cells significantly enhances proliferation by threefold in the remaining CD4(+)CD25(-) T cells, while the addition of isolated CD4(+)CD25(+) T cells to CD4(+)CD25(-) T cells significantly inhibits proliferative activity. Blocking experiments suggest that suppression is not mediated via IL-4, IL-10 or TGF-beta and is cell-contact dependent. Isolated CD4(+)CD25(+) T cells are susceptible to apoptosis that is associated with low Bcl-2 expression, but this death can be prevented by IL-2 or fibroblast-secreted IFN-beta. However, the anergic/suppressive state of these cells is maintained after cytokine rescue. These human regulatory cells are therefore a naturally occurring, highly suppressive, apoptosis-prone population which are at a late stage of differentiation. Further studies into their role in normal and pathological situations in humans are clearly essential.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis* / drug effects
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CD4 Antigens / immunology*
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CD4 Antigens / metabolism
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CD4-Positive T-Lymphocytes / cytology*
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CD4-Positive T-Lymphocytes / drug effects
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CD4-Positive T-Lymphocytes / immunology*
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CD4-Positive T-Lymphocytes / metabolism
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Cell Communication
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Cell Differentiation
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Cell Separation
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Cells, Cultured
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Clonal Anergy / immunology*
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Coculture Techniques
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Flow Cytometry
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Humans
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Immunophenotyping
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Immunosuppression Therapy*
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Interferon-beta / pharmacology
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Interleukin-10 / analysis
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Interleukin-10 / antagonists & inhibitors
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Interleukin-10 / immunology
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Interleukin-2 / immunology
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Interleukin-2 / pharmacology
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Interleukin-4 / analysis
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Interleukin-4 / immunology
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Palatine Tonsil / immunology
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Proto-Oncogene Proteins c-bcl-2 / analysis
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Receptors, Interleukin-2 / immunology*
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Receptors, Interleukin-2 / metabolism
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T-Lymphocyte Subsets / cytology
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T-Lymphocyte Subsets / drug effects
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism
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Transforming Growth Factor beta / analysis
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Transforming Growth Factor beta / antagonists & inhibitors
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Transforming Growth Factor beta / immunology
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bcl-X Protein
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fas Receptor / analysis
Substances
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BCL2L1 protein, human
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CD4 Antigens
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Interleukin-2
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Proto-Oncogene Proteins c-bcl-2
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Receptors, Interleukin-2
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Transforming Growth Factor beta
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bcl-X Protein
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fas Receptor
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Interleukin-10
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Interleukin-4
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Interferon-beta