Abstract
T cell receptor (TCR)-dependent regulatory T cell (Treg) activity controls effector T cell (Teff) function and is inhibited by the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). Protein kinase C-theta (PKC-theta) recruitment to the immunological synapse is required for full Teff activation. In contrast, PKC-theta was sequestered away from the Treg immunological synapse. Furthermore, PKC-theta blockade enhanced Treg function, demonstrating PKC-theta inhibits Treg-mediated suppression. Inhibition of PKC-theta protected Treg from inactivation by TNF-alpha, restored activity of defective Treg from rheumatoid arthritis patients, and enhanced protection of mice from inflammatory colitis. Treg freed of PKC-theta-mediated inhibition can function in the presence of inflammatory cytokines and thus have therapeutic potential in control of inflammatory diseases.
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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Adolescent
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Adult
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Aged
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Animals
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Arthritis, Rheumatoid / immunology
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Colitis / immunology
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Colitis / prevention & control
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Enzyme Inhibitors / pharmacology
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Feedback, Physiological
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Humans
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Immunological Synapses / immunology*
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Inflammation / immunology*
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Interferon-gamma / metabolism
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / metabolism*
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Lymphocyte Activation
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Mice
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Mice, Inbred C57BL
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Middle Aged
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Protein Kinase C / antagonists & inhibitors
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Protein Kinase C / metabolism*
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Receptors, Antigen, T-Cell / immunology
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Receptors, Antigen, T-Cell / metabolism
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Signal Transduction
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T-Lymphocyte Subsets / immunology*
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T-Lymphocyte Subsets / metabolism
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T-Lymphocytes, Regulatory / immunology*
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T-Lymphocytes, Regulatory / metabolism
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Tumor Necrosis Factor-alpha / metabolism
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Young Adult
Substances
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Enzyme Inhibitors
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Isoenzymes
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Receptors, Antigen, T-Cell
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Tumor Necrosis Factor-alpha
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Interferon-gamma
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Protein Kinase C