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

Regulatory T (T-reg) cells, which maintain immune homeostasis and self-tolerance, form an immunological synapse (IS) with antigen-presenting cells (APCs). However, signaling events at the T-reg cell IS remain unknown. Here we show that the kinase PKC-eta associated with CTLA-4 and was recruited to the T-reg cell IS. PKC-eta-deficient T-reg 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-eta and the GIT2-alpha PIX-PAK complex, an IS-localized focal adhesion complex. Defective activation of this complex in PKC-eta-deficient T-reg cells was associated with reduced depletion of CD86 from APCs by T-reg cells. These results reveal a CTLA-4-PKC-eta signaling axis required for contact-dependent suppression and implicate this pathway as a potential cancer immunotherapy target.