title: Association of CD147 and Calcium Exporter PMCA4 Uncouples IL-2 Expression from Early TCR Signaling.
abstract: The Ig superfamily member CD147 is upregulated following T cell activation and was shown to serve as a negative regulator of T cell proliferation. Thus, Abs targeting CD147 are being tested as new treatment strategies for cancer and autoimmune diseases. How CD147 mediates immunosuppression and whether association with other coreceptor complexes is needed have remained unknown. In the current study, we show that silencing of CD147 in human T cells increases IL-2 production without affecting the TCR proximal signaling components. We mapped the immunosuppressive moieties of CD147 to its transmembrane domain and Ig-like domain II. Using affinity purification combined with mass spectrometry, we determined the domain specificity of CD147 interaction partners and identified the calcium exporter plasma membrane calcium ATPase isoform 4 (PMCA4) as the interaction partner of the immunosuppressive moieties of CD147. CD147 does not control the proper membrane localization of PMCA4, but PMCA4 is essential for the CD147-dependent inhibition of IL-2 expression via a calcium-independent mechanism. In summary, our data show that CD147 interacts via its immunomodulatory domains with PMCA4 to bypass TCR proximal signaling and inhibit IL-2 expression.
authors.affiliation: Molecular Immunology Unit, Institute for Hygiene and Applied Immunology, Centre for Pathophysiology, Infectiology, and Immunology, Medical University of Vienna, 1090 Vienna, Austria;
authors.forename: Verena
authors.initials: V
authors.lastname: Supper
authors.affiliation: Molecular Immunology Unit, Institute for Hygiene and Applied Immunology, Centre for Pathophysiology, Infectiology, and Immunology, Medical University of Vienna, 1090 Vienna, Austria;
authors.forename: Herbert B
authors.initials: HB
authors.lastname: Schiller
authors.affiliation: Molecular Immunology Unit, Institute for Hygiene and Applied Immunology, Centre for Pathophysiology, Infectiology, and Immunology, Medical University of Vienna, 1090 Vienna, Austria;
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Paster
authors.affiliation: Molecular Immunology Unit, Institute for Hygiene and Applied Immunology, Centre for Pathophysiology, Infectiology, and Immunology, Medical University of Vienna, 1090 Vienna, Austria;
authors.forename: Florian
authors.initials: F
authors.lastname: Forster
authors.affiliation: Microchemistry Core Facility, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany;
authors.forename: Cyril
authors.initials: C
authors.lastname: Boulègue
authors.affiliation: Proteomics Core Facility, Medical University of Vienna, 1090 Vienna, Austria;
authors.forename: Goran
authors.identifier: http://orcid.org/0000-0003-1964-3965
authors.initials: G
authors.lastname: Mitulovic
authors.affiliation: Molecular Immunology Unit, Institute for Hygiene and Applied Immunology, Centre for Pathophysiology, Infectiology, and Immunology, Medical University of Vienna, 1090 Vienna, Austria; Institute of Molecular Biology, Slovak Academy of Sciences, 84551 Bratislava, Slovak Republic; and.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Leksa
authors.affiliation: Molecular Immunology Unit, Institute for Hygiene and Applied Immunology, Centre for Pathophysiology, Infectiology, and Immunology, Medical University of Vienna, 1090 Vienna, Austria;
authors.forename: Anna
authors.initials: A
authors.lastname: Ohradanova-Repic
authors.affiliation: Molecular Immunology Unit, Institute for Hygiene and Applied Immunology, Centre for Pathophysiology, Infectiology, and Immunology, Medical University of Vienna, 1090 Vienna, Austria;
authors.forename: Christian
authors.initials: C
authors.lastname: Machacek
authors.affiliation: Molecular Immunology Unit, Institute for Hygiene and Applied Immunology, Centre for Pathophysiology, Infectiology, and Immunology, Medical University of Vienna, 1090 Vienna, Austria;
authors.forename: Philipp
authors.initials: P
authors.lastname: Schatzlmaier
authors.affiliation: Institute of Immunology, Centre for Pathophysiology, Infectiology, and Immunology, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Gerhard J
authors.initials: GJ
authors.lastname: Zlabinger
authors.affiliation: Molecular Immunology Unit, Institute for Hygiene and Applied Immunology, Centre for Pathophysiology, Infectiology, and Immunology, Medical University of Vienna, 1090 Vienna, Austria; hannes.stockinger@meduniwien.ac.at.
authors.forename: Hannes
authors.identifier: http://orcid.org/0000-0001-6404-4430
authors.initials: H
authors.lastname: Stockinger
mesh_terms: D051926:Basigin / Q000276:immunology*; D002469:Cell Separation; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000276:immunology; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology*; D013058:Mass Spectrometry; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000276:immunology*; D060888:Real-Time Polymerase Chain Reaction; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014161:Transduction, Genetic
chemical_list: C497886:BSG protein, human; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D051926:Basigin; D053499:Plasma Membrane Calcium-Transporting ATPases