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

• Published in: Nature immunology Vol. 15; no. 5; pp. 465 - 472
• Main Authors: Kong, Kok-Fai, Fu, Guo, Zhang, Yaoyang, Yokosuka, Tadashi, Casas, Javier, Canonigo-Balancio, Ann J, Becart, Stephane, Kim, Gisen, Yates, John R, Kronenberg, Mitchell, Saito, Takashi, Gascoigne, Nicholas R J, Altman, Amnon
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.05.2014; Nature Publishing Group
• Subjects: 13; 13/1; 13/106; 13/109; 13/31; 13/44; 13/95; 14; 14/1; 14/34; 14/35; 631/250/516; 64; 64/60; 82/1; 82/29; 82/80; 96/95; Animals; Biomedicine; Cellular control mechanisms; CTLA-4 Antigen - metabolism; Humans; Immune Tolerance - genetics; Immunological Synapses - metabolism; Immunology; Immunotherapy - trends; Infectious Diseases; Jurkat Cells; Lymphocyte Activation; Melanoma, Experimental - immunology; Melanoma, Experimental - therapy; Mice; Mice, Inbred C57BL; Multiprotein Complexes - metabolism; Physiological aspects; Properties; Protein Binding; Protein Kinase C - genetics; Protein Kinase C - metabolism; Protein kinases; Proteomics; Signal Transduction; T cells; T-Lymphocytes, Regulatory - immunology; United Kingdom
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/ni.2866

Signaling events at the T reg cell immune synapse remain unknown. Altman and colleagues show that a CTLA-4–PKC-η signaling axis is required for contact-dependent suppression by T reg cells. Regulatory T (T reg ) cells, which maintain immune homeostasis and self-tolerance, form an immunological synapse (IS) with antigen-presenting cells (APCs). However, signaling events at the T reg cell IS remain unknown. Here we show that the kinase PKC-η associated with CTLA-4 and was recruited to the T reg cell IS. PKC-η–deficient T reg 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 T reg cells was associated with reduced depletion of CD86 from APCs by T reg 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.