Abstract
Regulatory T (Treg) cells have broad suppressive activity on host immunity, but the fate and function of suppressed responder T cells remains largely unknown. In the present study, we report that human Treg cells can induce senescence in responder naive and effector T cells in vitro and in vivo. Senescent responder T cells induced by human Treg cells changed their phenotypes and cytokine profiles and had potent suppressive function. Furthermore, Treg-mediated molecular control of senescence in responder T cells was associated with selective modulation of p38 and ERK1/2 signaling and cell-cycle-regulatory molecules p16, p21, and p53. We further revealed that human Treg-induced senescence and suppressor function could be blocked by TLR8 signaling and/or by specific ERK1/2 and p38 inhibition in vitro and in vivo in animal models. The results of the present study identify a novel mechanism of human Treg cell suppression that induces targeted responder T-cell senescence and provide new insights relevant for the development of strategies capable of preventing and/or reversing Treg-induced immune suppression.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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CD4-Positive T-Lymphocytes / immunology*
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CD4-Positive T-Lymphocytes / metabolism
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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 Cycle / immunology
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Cellular Senescence / immunology*
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Coculture Techniques
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Cyclin-Dependent Kinase Inhibitor p16
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Cyclin-Dependent Kinase Inhibitor p21 / genetics
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Cyclin-Dependent Kinase Inhibitor p21 / immunology
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Cytokines / biosynthesis
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Cytokines / immunology
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Gene Expression / immunology
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Humans
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Immunity, Innate
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Lymphocyte Activation
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MAP Kinase Signaling System / immunology*
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Mice
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Mice, Knockout
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Neoplasm Proteins / genetics
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Neoplasm Proteins / immunology
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Primary Cell Culture
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T-Lymphocytes, Regulatory / immunology*
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T-Lymphocytes, Regulatory / metabolism
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Toll-Like Receptor 8 / genetics
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Toll-Like Receptor 8 / immunology
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / immunology
Substances
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CDKN1A protein, human
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CDKN2A protein, human
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Cyclin-Dependent Kinase Inhibitor p16
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Cyclin-Dependent Kinase Inhibitor p21
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Cytokines
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Neoplasm Proteins
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TLR8 protein, human
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Toll-Like Receptor 8
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Tumor Suppressor Protein p53