title: MERTK as negative regulator of human T cell activation.
abstract: The aim of this study was to test the hypothesis whether MERTK, which is up-regulated in human DCs treated with immunosuppressive agents, is directly involved in modulating T cell activation. MERTK is a member of the TAM family and contributes to regulating innate immune response to ACs by inhibiting DC activation in animal models. However, whether MERTK interacts directly with T cells has not been addressed. Here, we show that MERTK is highly expressed on dex-induced human tol-DCs and participates in their tolerogenic effect. Neutralization of MERTK in allogenic MLR, as well as autologous DC-T cell cultures, leads to increased T cell proliferation and IFN-γ production. Additionally, we identify a previously unrecognized noncell-autonomous regulatory function of MERTK expressed on DCs. Mer-Fc protein, used to mimic MERTK on DCs, suppresses naïve and antigen-specific memory T cell activation. This mechanism is mediated by the neutralization of the MERTK ligand PROS1. We find that MERTK and PROS1 are expressed in human T cells upon TCR activation and drive an autocrine proproliferative mechanism. Collectively, these results suggest that MERTK on DCs controls T cell activation and expansion through the competition for PROS1 interaction with MERTK in the T cells. In conclusion, this report identified MERTK as a potent suppressor of T cell response.
authors.affiliation: *Fundació Clínic per a la Recerca Biomèdica, Barcelona, Spain; Instituto de Medicina Experimental, Academia Nacional de Medicina, Buenos Aires, Argentina; Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; 3ra Cátedra de Farmacologia, Facultad de Medicina, Universidad de Buenos Aires, Argentina; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain; Department of Gastroenterology, Hospital Clínic de Barcelona, Spain; and Department of Immunobiology, Yale University, New Haven, Connecticut, USA.
authors.forename: Raquel
authors.initials: R
authors.lastname: Cabezón
authors.affiliation: *Fundació Clínic per a la Recerca Biomèdica, Barcelona, Spain; Instituto de Medicina Experimental, Academia Nacional de Medicina, Buenos Aires, Argentina; Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; 3ra Cátedra de Farmacologia, Facultad de Medicina, Universidad de Buenos Aires, Argentina; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain; Department of Gastroenterology, Hospital Clínic de Barcelona, Spain; and Department of Immunobiology, Yale University, New Haven, Connecticut, USA.
authors.forename: E Antonio
authors.initials: EA
authors.lastname: Carrera-Silva
authors.affiliation: *Fundació Clínic per a la Recerca Biomèdica, Barcelona, Spain; Instituto de Medicina Experimental, Academia Nacional de Medicina, Buenos Aires, Argentina; Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; 3ra Cátedra de Farmacologia, Facultad de Medicina, Universidad de Buenos Aires, Argentina; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain; Department of Gastroenterology, Hospital Clínic de Barcelona, Spain; and Department of Immunobiology, Yale University, New Haven, Connecticut, USA.
authors.forename: Georgina
authors.initials: G
authors.lastname: Flórez-Grau
authors.affiliation: *Fundació Clínic per a la Recerca Biomèdica, Barcelona, Spain; Instituto de Medicina Experimental, Academia Nacional de Medicina, Buenos Aires, Argentina; Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; 3ra Cátedra de Farmacologia, Facultad de Medicina, Universidad de Buenos Aires, Argentina; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain; Department of Gastroenterology, Hospital Clínic de Barcelona, Spain; and Department of Immunobiology, Yale University, New Haven, Connecticut, USA.
authors.forename: Andrea E
authors.initials: AE
authors.lastname: Errasti
authors.affiliation: *Fundació Clínic per a la Recerca Biomèdica, Barcelona, Spain; Instituto de Medicina Experimental, Academia Nacional de Medicina, Buenos Aires, Argentina; Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; 3ra Cátedra de Farmacologia, Facultad de Medicina, Universidad de Buenos Aires, Argentina; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain; Department of Gastroenterology, Hospital Clínic de Barcelona, Spain; and Department of Immunobiology, Yale University, New Haven, Connecticut, USA.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Calderón-Gómez
authors.affiliation: *Fundació Clínic per a la Recerca Biomèdica, Barcelona, Spain; Instituto de Medicina Experimental, Academia Nacional de Medicina, Buenos Aires, Argentina; Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; 3ra Cátedra de Farmacologia, Facultad de Medicina, Universidad de Buenos Aires, Argentina; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain; Department of Gastroenterology, Hospital Clínic de Barcelona, Spain; and Department of Immunobiology, Yale University, New Haven, Connecticut, USA.
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Lozano
authors.affiliation: *Fundació Clínic per a la Recerca Biomèdica, Barcelona, Spain; Instituto de Medicina Experimental, Academia Nacional de Medicina, Buenos Aires, Argentina; Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; 3ra Cátedra de Farmacologia, Facultad de Medicina, Universidad de Buenos Aires, Argentina; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain; Department of Gastroenterology, Hospital Clínic de Barcelona, Spain; and Department of Immunobiology, Yale University, New Haven, Connecticut, USA.
authors.forename: Carolina
authors.initials: C
authors.lastname: España
authors.affiliation: *Fundació Clínic per a la Recerca Biomèdica, Barcelona, Spain; Instituto de Medicina Experimental, Academia Nacional de Medicina, Buenos Aires, Argentina; Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; 3ra Cátedra de Farmacologia, Facultad de Medicina, Universidad de Buenos Aires, Argentina; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain; Department of Gastroenterology, Hospital Clínic de Barcelona, Spain; and Department of Immunobiology, Yale University, New Haven, Connecticut, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Ricart
authors.affiliation: *Fundació Clínic per a la Recerca Biomèdica, Barcelona, Spain; Instituto de Medicina Experimental, Academia Nacional de Medicina, Buenos Aires, Argentina; Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; 3ra Cátedra de Farmacologia, Facultad de Medicina, Universidad de Buenos Aires, Argentina; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain; Department of Gastroenterology, Hospital Clínic de Barcelona, Spain; and Department of Immunobiology, Yale University, New Haven, Connecticut, USA.
authors.forename: Julián
authors.initials: J
authors.lastname: Panés
authors.affiliation: *Fundació Clínic per a la Recerca Biomèdica, Barcelona, Spain; Instituto de Medicina Experimental, Academia Nacional de Medicina, Buenos Aires, Argentina; Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; 3ra Cátedra de Farmacologia, Facultad de Medicina, Universidad de Buenos Aires, Argentina; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain; Department of Gastroenterology, Hospital Clínic de Barcelona, Spain; and Department of Immunobiology, Yale University, New Haven, Connecticut, USA.
authors.forename: Carla Vanina
authors.initials: CV
authors.lastname: Rothlin
authors.affiliation: *Fundació Clínic per a la Recerca Biomèdica, Barcelona, Spain; Instituto de Medicina Experimental, Academia Nacional de Medicina, Buenos Aires, Argentina; Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; 3ra Cátedra de Farmacologia, Facultad de Medicina, Universidad de Buenos Aires, Argentina; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain; Department of Gastroenterology, Hospital Clínic de Barcelona, Spain; and Department of Immunobiology, Yale University, New Haven, Connecticut, USA. daniel.benitez@ciberehd.org.
authors.forename: Daniel
authors.initials: D
authors.lastname: Benítez-Ribas
mesh_terms: D000942:Antigens, Bacterial / Q000276:immunology; D019898:Autocrine Communication; D001798:Blood Proteins / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000201:enzymology*; D002454:Cell Differentiation; D002455:Cell Division; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D003907:Dexamethasone / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D007108:Immune Tolerance / Q000502:physiology*; D007156:Immunologic Memory; D059425:Interferon-gamma Release Tests; D008213:Lymphocyte Activation / Q000502:physiology*; D007959:Lymphocyte Culture Test, Mixed; D009000:Monocytes / Q000166:cytology; D017293:Protein S; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D037182:T-Cell Antigen Receptor Specificity; D015854:Up-Regulation / Q000187:drug effects; D000076202:c-Mer Tyrosine Kinase
chemical_list: D000942:Antigens, Bacterial; D001798:Blood Proteins; C523390:PROS1 protein, human; D017293:Protein S; D011518:Proto-Oncogene Proteins; D003907:Dexamethasone; C097072:MERTK protein, human; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase
keywords: TAM receptors; suppression; tolerogenic dendritic cells