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Science 328 (5976): 372-376

Copyright © 2010 by the American Association for the Advancement of Science

Protein Kinase C-{theta} Mediates Negative Feedback on Regulatory T Cell Function

Alexandra Zanin-Zhorov,1 Yi Ding,1 Sudha Kumari,1 Mukundan Attur,2 Keli L. Hippen,3 Maryanne Brown,4 Bruce R. Blazar,3 Steven B. Abramson,2 Juan J. Lafaille,1 Michael L. Dustin1,*

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.

1 Molecular Pathogenesis Program, Helen and Martin Kimmel Center for Biology and Medicine, Skirball Institute of Biomolecular Medicine, Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
2 Division of Rheumatology, New York University School of Medicine and New York University Hospital for Joint Diseases, New York, NY 10003, USA.
3 University of Minnesota Cancer Center and Department of Pediatrics, Division of Bone, Blood and Marrow Transplantation, Minneapolis, MN 55455, USA.
4 Boehringer Ingelheim, Ridgefield, CT 06877, USA.

* To whom correspondence should be addressed. E-mail: michael.dustin{at}med.nyu.edu

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