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. Epub 2014 Apr 6.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CTLA-4 Antigen / metabolism*
  • Humans
  • Immune Tolerance / genetics
  • Immunological Synapses / metabolism*
  • Immunotherapy / trends*
  • Jurkat Cells
  • Lymphocyte Activation
  • Melanoma, Experimental / immunology*
  • Melanoma, Experimental / therapy*
  • Mice
  • Mice, Inbred C57BL
  • Multiprotein Complexes / metabolism*
  • Protein Binding
  • Protein Kinase C / genetics
  • Protein Kinase C / metabolism*
  • Proteomics
  • Signal Transduction
  • T-Lymphocytes, Regulatory / immunology*


  • CTLA-4 Antigen
  • Multiprotein Complexes
  • protein kinase C eta
  • Protein Kinase C