Protein Kinase C-θ Mediates Negative Feedback on Regulatory T Cell Function

T cell receptor (TCR)-dependent regulatory T cell (T-reg) activity controls effector T cell (T-eff) 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 T-eff activation. In contrast, PKC-theta was sequestered away from the T-reg immunological synapse. Furthermore, PKC-theta blockade enhanced T-reg function, demonstrating PKC-theta inhibits T-reg-mediated suppression. Inhibition of PKC-theta protected T-reg from inactivation by TNF-alpha, restored activity of defective T-reg from rheumatoid arthritis patients, and enhanced protection of mice from inflammatory colitis. T-reg freed of PKC-theta-mediated inhibition can function in the presence of inflammatory cytokines and thus have therapeutic potential in control of inflammatory diseases.