Abstract
Abstract T cell receptor (TCR) dependent regulatory T cell (Treg) activity controls effector T cell (Teff) function and is acutely inhibited by tumor necrosis factor (TNF). Protein kinase C-θ (PKC-θ) recruitment to the immunological synapse is required in effector cells to recruit Carma-1 in the pathway to NF-κB activation. Surprisingly, PKC-θ was sequestered away from the Treg immunological synapse. Furthermore, PKC-θ inhibition or suppression by RNAi enhanced Treg function, demonstrating PKC-θ mediated negative feedback. Treg integrate TCR and TNF signals through control of PKC-θ location such that inhibition of PKC-θ protected Treg from inactivation by TNF, restored activity of defective Treg from rheumatoid arthritis patients, and enhanced protection of mice from inflammatory colitis. Treg freed of PKC-θ mediated negative feedback can function in the presence of TNF and thus have therapeutic potential in control of inflammatory diseases.
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