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

Alexandra Zanin-Zhorov, Yi Ding, Sudha Kumari, Mukundan Attur, Keli L. Hippen, Maryanne Brown, Bruce R. Blazar, Steven B. Abramson, Juan J. Lafaille, Michael L. Dustin

Research output: Contribution to journalArticle

206 Scopus citations

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-a (TNF-a Protein kinase C-θ (PKC-θ) recruitment to the immunological synapse is required for full Teff activation. In contrast, PKC-6 was sequestered away from the Treg immunological synapse. Furthermore, PKC-θ blockade enhanced Treg function, demonstrating PKC-6 inhibits T reg-mediated suppression. Inhibition of PKC-6 protected T reg from inactivation by TNF-a, restored activity of defective T reg from rheumatoid arthritis patients, and enhanced protection of mice from inflammatory colitis. Treg freed of PKC-6-mediated inhibition can function in the presence of inflammatory cytokines and thus have therapeutic potential in control of inflammatory diseases.

Original languageEnglish (US)
Pages (from-to)372-376
Number of pages5
JournalScience
Volume328
Issue number5976
DOIs
StatePublished - Apr 16 2010

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    Zanin-Zhorov, A., Ding, Y., Kumari, S., Attur, M., Hippen, K. L., Brown, M., Blazar, B. R., Abramson, S. B., Lafaille, J. J., & Dustin, M. L. (2010). Protein kinase C-θ mediates negative feedback on regulatory T cell function. Science, 328(5976), 372-376. https://doi.org/10.1126/science.1186068