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

KF Kong, G Fu, Y Zhang, T Yokosuka, J Casas… - Nature …, 2014 - nature.com
KF Kong, G Fu, Y Zhang, T Yokosuka, J Casas, AJ Canonigo-Balancio, S Becart, G Kim…
Nature immunology, 2014nature.com
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 revealed an association …
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-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 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 Treg cells was associated with reduced depletion of CD86 from APCs by Treg 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.
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