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Nat Immunol. 2014 May;15(5):465-72. doi: 10.1038/ni.2866. Epub 2014 Apr 6.

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

Author information

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].

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.

Comment in

PMID:
24705298
PMCID:
PMC4040250
DOI:
10.1038/ni.2866
[Indexed for MEDLINE]
Free PMC Article

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