title: Hepatocyte Growth Factor Receptor c-Met Instructs T Cell Cardiotropism and Promotes T Cell Migration to the Heart via Autocrine Chemokine Release.
abstract: Effector-T-cell-mediated immunity depends on the efficient localization of antigen-primed lymphocytes to antigen-rich non-lymphoid tissue, which is facilitated by the expression of a unique set of "homing" receptors acquired by memory T cells. We report that engagement of the hepatocyte growth factor (HGF) receptor c-Met by heart-produced HGF during priming in the lymph nodes instructs T cell cardiotropism, which was associated with a specialized homing "signature" (c-Met(+)CCR4(+)CXCR3(+)). c-Met signals facilitated T cell recruitment to the heart via the chemokine receptor CCR5 by inducing autocrine CCR5 ligand release. c-Met triggering was sufficient to support cardiotropic T cell recirculation, while CCR4 and CXCR3 sustained recruitment during heart inflammation. Transient pharmacological blockade of c-Met during T cell priming led to enhanced survival of heart, but not skin, allografts associated with impaired localization of alloreactive T cells to heart grafts. These findings suggest c-Met as a target for development of organ-selective immunosuppressive therapies.
authors.affiliation: William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
authors.forename: Izabela
authors.initials: I
authors.lastname: Komarowska
authors.affiliation: William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
authors.forename: David
authors.initials: D
authors.lastname: Coe
authors.affiliation: William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
authors.forename: Guosu
authors.initials: G
authors.lastname: Wang
authors.affiliation: William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Haas
authors.affiliation: William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
authors.forename: Claudio
authors.initials: C
authors.lastname: Mauro
authors.affiliation: William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
authors.forename: Madhav
authors.initials: M
authors.lastname: Kishore
authors.affiliation: William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
authors.forename: Dianne
authors.initials: D
authors.lastname: Cooper
authors.affiliation: William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
authors.forename: Suchita
authors.initials: S
authors.lastname: Nadkarni
authors.affiliation: William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Fu
authors.affiliation: Department of Thoracic Surgery, Copenhagen University Hospital, 2100 Copenhagen, Denmark.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Steinbruchel
authors.affiliation: William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
authors.forename: Costantino
authors.initials: C
authors.lastname: Pitzalis
authors.affiliation: MRC Centre for Immune Regulation, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Graham
authors.initials: G
authors.lastname: Anderson
authors.affiliation: University of Alabama at Birmingham, Birmingham, AL 35233, USA.
authors.forename: Pat
authors.initials: P
authors.lastname: Bucy
authors.affiliation: MRC Centre for Transplantation, King's College London, London SE1 1UL, UK.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Lombardi
authors.affiliation: Division of Medicine, University College London, BHF Labs, London WC1E 6JJ, UK.
authors.forename: Ross
authors.initials: R
authors.lastname: Breckenridge
authors.affiliation: William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK. Electronic address: f.marelli-berg@qmul.ac.uk.
authors.forename: Federica M
authors.initials: FM
authors.lastname: Marelli-Berg
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D006084:Graft Rejection / Q000209:etiology / Q000235:genetics / Q000517:prevention & control*; D006321:Heart / Q000502:physiology*; D016027:Heart Transplantation; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D007156:Immunologic Memory; D007211:Indoles / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D051379:Mice; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D019713:Receptors, CCR5 / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism; D016201:Receptors, Lymphocyte Homing / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013450:Sulfones / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology*
chemical_list: C480541:5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one; C000592874:CCR5 protein, mouse; D007211:Indoles; D034741:RNA, Small Interfering; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D016201:Receptors, Lymphocyte Homing; D013450:Sulfones; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met