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Protein kinase C-? controls CTLA-4-mediated regulatory T cell function.

ABSTRACT: Regulatory T (Treg) cells, which maintain immune homeostasis and self-tolerance, form an immunological synapse (IS) with antigen-presenting cells (APCs). However, signaling events at the Treg cell IS remain unknown. Here we show that the kinase PKC-? associated with CTLA-4 and was recruited to the Treg cell IS. PKC-?-deficient Treg cells displayed defective suppressive activity, including suppression of tumor immunity but not of autoimmune colitis. Phosphoproteomic and biochemical analysis revealed an association between CTLA-4-PKC-? and the GIT2-?PIX-PAK complex, an IS-localized focal adhesion complex. Defective activation of this complex in PKC-?-deficient Treg cells was associated with reduced depletion of CD86 from APCs by Treg cells. These results reveal a CTLA-4-PKC-? signaling axis required for contact-dependent suppression and implicate this pathway as a potential cancer immunotherapy target.

SUBMITTER: Kong KF 

PROVIDER: S-EPMC4040250 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Regulatory T (Treg) cells, which maintain immune homeostasis and self-tolerance, form an immunological synapse (IS) with antigen-presenting cells (APCs). However, signaling events at the Treg cell IS remain unknown. Here we show that the kinase PKC-η associated with CTLA-4 and was recruited to the Treg cell IS. PKC-η-deficient Treg cells displayed defective suppressive activity, including suppression of tumor immunity but not of autoimmune colitis. Phosphoproteomic and biochemical analysis revea  ...[more]

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