title: The late endosomal transporter CD222 directs the spatial distribution and activity of Lck.
abstract: The spatial and temporal organization of T cell signaling molecules is increasingly accepted as a crucial step in controlling T cell activation. CD222, also known as the cation-independent mannose 6-phosphate/insulin-like growth factor 2 receptor, is the central component of endosomal transport pathways. In this study, we show that CD222 is a key regulator of the early T cell signaling cascade. Knockdown of CD222 hampers the effective progression of TCR-induced signaling and subsequent effector functions, which can be rescued via reconstitution of CD222 expression. We decipher that Lck is retained in the cytosol of CD222-deficient cells, which obstructs the recruitment of Lck to CD45 at the cell surface, resulting in an abundant inhibitory phosphorylation signature on Lck at the steady state. Hence, CD222 specifically controls the balance between active and inactive Lck in resting T cells, which guarantees operative T cell effector functions.
authors.affiliation: Molecular Immunology Unit, Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna A-1090, Austria;
authors.forename: Karin
authors.initials: K
authors.lastname: Pfisterer
authors.affiliation: Molecular Immunology Unit, Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna A-1090, Austria;
authors.forename: Florian
authors.initials: F
authors.lastname: Forster
authors.affiliation: Molecular Immunology Unit, Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna A-1090, Austria; Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom;
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Paster
authors.affiliation: Molecular Immunology Unit, Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna A-1090, Austria;
authors.forename: Verena
authors.initials: V
authors.lastname: Supper
authors.affiliation: Molecular Immunology Unit, Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna A-1090, Austria;
authors.forename: Anna
authors.initials: A
authors.lastname: Ohradanova-Repic
authors.affiliation: Molecular Immunology Unit, Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna A-1090, Austria;
authors.forename: Paul
authors.initials: P
authors.lastname: Eckerstorfer
authors.affiliation: Molecular Immunology Unit, Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna A-1090, Austria;
authors.forename: Alexander
authors.initials: A
authors.lastname: Zwirzitz
authors.affiliation: Molecular Immunology Unit, Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna A-1090, Austria;
authors.forename: Clemens
authors.initials: C
authors.lastname: Donner
authors.affiliation: Department of Molecular Medicine, Max-Planck Institute of Biochemistry, Martinsried 82152, Germany; and.
authors.forename: Cyril
authors.initials: C
authors.lastname: Boulegue
authors.affiliation: Molecular Immunology Unit, Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna A-1090, Austria; Department of Molecular Medicine, Max-Planck Institute of Biochemistry, Martinsried 82152, Germany; and.
authors.forename: Herbert B
authors.initials: HB
authors.lastname: Schiller
authors.affiliation: Laboratory of Molecular Immunology, Institute of Molecular Biology, Slovak Academy of Sciences, 84551 Bratislava, Slovak Republic.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Ondrovičová
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom;
authors.forename: Oreste
authors.initials: O
authors.lastname: Acuto
authors.affiliation: Molecular Immunology Unit, Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna A-1090, Austria; vladimir.leksa@meduniwien.ac.at hannes.stockinger@meduniwien.ac.at.
authors.forename: Hannes
authors.initials: H
authors.lastname: Stockinger
authors.affiliation: Molecular Immunology Unit, Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna A-1090, Austria; Laboratory of Molecular Immunology, Institute of Molecular Biology, Slovak Academy of Sciences, 84551 Bratislava, Slovak Republic vladimir.leksa@meduniwien.ac.at hannes.stockinger@meduniwien.ac.at.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Leksa
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D019169:Jurkat Cells; D017493:Leukocyte Common Antigens / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000235:genetics / Q000276:immunology*; D026901:Membrane Transport Proteins / Q000276:immunology; D051379:Mice; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering; D017527:Receptor, IGF Type 2 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D026901:Membrane Transport Proteins; D034741:RNA, Small Interfering; D017527:Receptor, IGF Type 2; D011948:Receptors, Antigen, T-Cell; C034304:cation-dependent mannose-6-phosphate receptor; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D017493:Leukocyte Common Antigens; C516769:PTPRC protein, human