Protein kinase C-theta mediates negative feedback on regulatory T cell function.

Journal article

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.

Authors: Zanin-Zhorov, A; Ding, Y; Kumari, S; Attur, M; Hippen, K

• Journal: Science (New York, N.Y.)
• Volume: 328
• Issue: 5976
• Pages: 372-376
• Publication date: 2010-04-01
• DOI: 10.1126/science.1186068
• EISSN: 1095-9203
• ISSN: 0036-8075
• Language: English
• Keywords: Adolescent; Enzyme Inhibitors; Signal Transduction; Protein Kinase C; Humans; Tumor Necrosis Factor-alpha; Young Adult; Arthritis, Rheumatoid; Isoenzymes; Adult; Middle Aged; Aged; Animals; Inflammation; Mice, Inbred C57BL; Feedback, Physiological; Lymphocyte Activation; Receptors, Antigen, T-Cell; T-Lymphocyte Subsets; Interferon-gamma; Mice; T-Lymphocytes, Regulatory; Immunological Synapses; Colitis