Abstract
Continuous antigen stimulation of CD4(+)CD25(-) T cells leads to generation of adaptive CD4(+)CD25(+)FOXP3(+) regulatory T (T(R)) cells. Here, we show that highly suppressive adaptive CD8(+)CD25(+)FOXP3(+) T cells can be generated in the same manner by continuous antigen stimulation in the presence of CD14(+) monocytes. During the course of stimulation, acquisition of immunosuppressive properties develops in parallel with up-regulation and expression of cytotoxic molecules. The CD8(+) T(R) cells inhibit CD4(+) and CD8(+) T cell proliferation and cytokine production, but do not alter the expression of granzyme A and granzyme B or perforin in CD8(+) effector T cells. Although, the CD8(+) T(R) cells express prostaglandin E(2), IL-10 and TGF-beta, the mechanism of suppression was independent of these soluble factors. In contrast to adaptive CD4(+) T(R) cells, the CD8(+) T(R) cells suppress mainly by a contact-dependent mechanism as evident from transwell experiments. However, neither blocking antibodies to CTLA-4, CD80 nor CD86 could reverse CD8(+) T(R)-mediated suppression, indicating that other mechanism(s) must be employed by these cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antibodies / immunology
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Antibodies / pharmacology
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Antigens, Bacterial / immunology
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CD28 Antigens / analysis
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CD4-Positive T-Lymphocytes / chemistry
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CD4-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / chemistry
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / metabolism
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Cell Communication / immunology
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Cell Differentiation / immunology
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Dinoprostone / antagonists & inhibitors
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Dinoprostone / metabolism
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Enterotoxins / immunology
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Forkhead Transcription Factors / analysis*
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Glucocorticoid-Induced TNFR-Related Protein
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Granzymes / metabolism
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Humans
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Immune Tolerance / drug effects
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Immune Tolerance / immunology
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Immunophenotyping
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Interleukin-10 / immunology
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Interleukin-10 / metabolism
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Interleukin-2 Receptor alpha Subunit / analysis*
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Leukocytes, Mononuclear / immunology
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Monocytes / immunology
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Perforin / metabolism
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Receptors, Nerve Growth Factor / analysis
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Receptors, Tumor Necrosis Factor / analysis
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T-Lymphocyte Subsets / chemistry
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism
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T-Lymphocytes, Regulatory / chemistry
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T-Lymphocytes, Regulatory / immunology*
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T-Lymphocytes, Regulatory / metabolism
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Transforming Growth Factor beta / immunology
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Transforming Growth Factor beta / metabolism
Substances
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Antibodies
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Antigens, Bacterial
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CD28 Antigens
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Enterotoxins
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FOXP3 protein, human
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Forkhead Transcription Factors
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Glucocorticoid-Induced TNFR-Related Protein
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Interleukin-2 Receptor alpha Subunit
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Receptors, Nerve Growth Factor
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Receptors, Tumor Necrosis Factor
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TNFRSF18 protein, human
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Transforming Growth Factor beta
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Perforin
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Interleukin-10
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enterotoxin B, staphylococcal
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Granzymes
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Dinoprostone