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

Signaling events at the T reg cell immune synapse remain unknown. Altman and colleagues show that a CTLA-4–PKC-η signaling axis is required for contact-dependent suppression by T reg cells. 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-η associated with CTLA-4 and was recruited to the T reg cell IS. PKC-η–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-η and the GIT2-αPIX-PAK complex, an IS-localized focal adhesion complex. Defective activation of this complex in PKC-η–deficient T reg cells was associated with reduced depletion of CD86 from APCs by T reg cells. These results reveal a CTLA-4–PKC-η signaling axis required for contact-dependent suppression and implicate this pathway as a potential cancer immunotherapy target.