Protein kinase C-η controls CTLA-4-mediated regulatory T cell function.
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.
1] Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA. [2].
Kok-Fai
KF
Kong
1] Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, USA. [2].
Guo
G
Fu
Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA.
Yaoyang
Y
Zhang
1] RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. [2] PRESTO, Japan Science and Technology Agency, Saitama, Japan.
Tadashi
T
Yokosuka
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, USA.
Javier
J
Casas
Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
Ann J
AJ
Canonigo-Balancio
Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
Stephane
S
Becart
Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
Gisen
G
Kim
Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA.
John R
JR
Yates
Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
Mitchell
M
Kronenberg
RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Takashi
T
Saito
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].
Nicholas R J
0000000199804225
NR
Gascoigne
1] Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA. [2].
Amnon
A
Altman
D000818:Animals; D060908:CTLA-4 Antigen / Q000378:metabolism*; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D054992:Immunological Synapses / Q000378:metabolism*; D007167:Immunotherapy / Q000639:trends*; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D008546:Melanoma, Experimental / Q000276:immunology* / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000378:metabolism*; D011485:Protein Binding; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D040901:Proteomics; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D060908:CTLA-4 Antigen; D046912:Multiprotein Complexes; C081975:protein kinase C eta; D011493:Protein Kinase C