Abstract
Nonantigen specific CD8+ suppressor T lymphocytes (CD8+ Ts) inhibit T-cell proliferation of antigen-specific T lymphocytes. The impossibility to generate in vitro these cells has been correlated with the appearance of relapses in patients affected by autoimmune diseases, suggesting the involvement of these cells in immune regulation. This study was aimed to identify circulating precursors and to characterize the phenotype and mechanism of action of CD8+ Ts. We found that CD8+ Ts can be generated in vitro from CD8+CD28- T lymphocytes, but not from CD8+CD28+ T cells. A key role in their generation is played by monocytes that secrete interleukin-10 (IL-10) after granulocyte macrophage-colony-stimulating factor (GM-CSF) stimulation. Cell-to-cell direct interaction between CD8+CD28- T cells and monocytes does not play a role in the generation of CD8+ Ts. CD8+ Ts have a CD45RA+, CD27-, CCR7-, IL-10Ralpha+ phenotype and a TCR Vbeta chain repertoire overlapping that of autologous circulating CD8+ T cells. This phenotype is typical of T lymphocytes previously expanded due to antigen stimulation. Their suppressive effect on T-cell proliferation targets both antigen presenting cells, such as dendritic cells, and antigen-specific T lymphocytes, and is mediated by IL-10. CD8+ Ts suppress also the antigen-specific cytotoxic activity of CTL decreasing the expression of HLA class I molecules on target cells through IL-10 secretion. These findings can be helpful for the better understanding of immune regulatory circuits and for the definition of new pathogenic aspects in autoimmunity and tumor immunology.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antibodies, Monoclonal / pharmacology
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Antibody-Dependent Cell Cytotoxicity / drug effects
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Antibody-Dependent Cell Cytotoxicity / immunology
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Antigen Presentation / drug effects
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Antigen Presentation / immunology
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CD28 Antigens / analysis
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CD28 Antigens / immunology*
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CD3 Complex / immunology
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CD4-Positive T-Lymphocytes / drug effects
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CD4-Positive T-Lymphocytes / immunology
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CD8 Antigens / analysis
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CD8-Positive T-Lymphocytes / drug effects
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CD8-Positive T-Lymphocytes / immunology*
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Cell Communication / immunology
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Cell Differentiation / drug effects
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Cell Differentiation / immunology
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Cell Proliferation / drug effects
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Coculture Techniques
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Culture Media, Conditioned / pharmacology
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Dendritic Cells / drug effects
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Dendritic Cells / immunology
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Flow Cytometry
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Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
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Histocompatibility Antigens Class I / immunology
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Histocompatibility Antigens Class I / 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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Immune Tolerance / physiology
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Interleukin-10 / immunology
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Interleukin-10 / metabolism
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Interleukin-10 / physiology
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Interleukin-2 / pharmacology
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Leukocyte Common Antigens / analysis
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Lymphocyte Activation / drug effects
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Lymphocyte Activation / immunology
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Lymphocyte Activation / physiology
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Monocytes / immunology
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Monocytes / metabolism
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Monocytes / radiation effects
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Receptors, Antigen, T-Cell, alpha-beta / analysis
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Receptors, CCR7
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Receptors, Chemokine / analysis
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Receptors, Interleukin / analysis
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Receptors, Interleukin-10
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T-Lymphocytes / cytology
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T-Lymphocytes / drug effects
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T-Lymphocytes / immunology*
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T-Lymphocytes, Cytotoxic / cytology
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T-Lymphocytes, Cytotoxic / drug effects
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T-Lymphocytes, Cytotoxic / immunology
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T-Lymphocytes, Regulatory / cytology
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T-Lymphocytes, Regulatory / drug effects
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T-Lymphocytes, Regulatory / immunology*
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Tuberculin / immunology
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Tumor Necrosis Factor Receptor Superfamily, Member 7 / analysis
Substances
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Antibodies, Monoclonal
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CCR7 protein, human
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CD28 Antigens
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CD3 Complex
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CD8 Antigens
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Culture Media, Conditioned
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Histocompatibility Antigens Class I
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Interleukin-2
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Receptors, Antigen, T-Cell, alpha-beta
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Receptors, CCR7
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Receptors, Chemokine
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Receptors, Interleukin
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Receptors, Interleukin-10
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Tuberculin
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Tumor Necrosis Factor Receptor Superfamily, Member 7
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Interleukin-10
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Granulocyte-Macrophage Colony-Stimulating Factor
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Leukocyte Common Antigens