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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.

Original publication

DOI

10.1126/science.1186068

Type

Journal article

Journal

Science

Publication Date

16/04/2010

Volume

328

Pages

372 - 376

Keywords

Adolescent, Adult, Aged, Animals, Arthritis, Rheumatoid, Colitis, Enzyme Inhibitors, Feedback, Physiological, Humans, Immunological Synapses, Inflammation, Interferon-gamma, Isoenzymes, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Middle Aged, Protein Kinase C, Receptors, Antigen, T-Cell, Signal Transduction, T-Lymphocyte Subsets, T-Lymphocytes, Regulatory, Tumor Necrosis Factor-alpha, Young Adult