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

  • Nat Immunol. 2014 May;15(5):465-72. doi: 10.1038/ni.2866.
Kok-Fai Kong  1 ,  Guo Fu  2 ,  Yaoyang Zhang  3 ,  Tadashi Yokosuka  4 ,  Javier Casas  5 ,  Ann J Canonigo-Balancio  6 ,  Stephane Becart  6 ,  Gisen Kim  7 ,  John R Yates 3rd  3 ,  Mitchell Kronenberg  7 ,  Takashi Saito  8 ,  Nicholas R J Gascoigne  9 ,  Amnon Altman  1
Affiliations
  • 1. 1] Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA. [2].
  • 2. 1] Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, USA. [2].
  • 3. Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA.
  • 4. 1] RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. [2] PRESTO, Japan Science and Technology Agency, Saitama, Japan.
  • 5. Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, USA.
  • 6. Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
  • 7. Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
  • 8. RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
  • 9. 1] Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, USA. [2] Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA. [3] [4].
PMID: 24705298 DOI: 10.1038/ni.2866
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.