title: Immunotherapeutic targeting of LIGHT/LTβR/HVEM pathway fully recapitulates the reduced cytotoxic phenotype of LIGHT-deficient T cells.
abstract: Tumor necrosis factor (TNF)/TNF receptor (TNFR) superfamily members play essential roles in the development of the different phases of the immune response. Mouse LIGHT (TNFSF14) is a type II transmembrane protein with a C-terminus extracellular TNF homology domain (THD) that assembles in homotrimers and regulates the course of the immune responses by signaling through 2 receptors, the herpes virus entry mediator (HVEM, TNFRSF14) and the lymphotoxin β receptor (LTβR, TNFRSF3). LIGHT is a membrane-bound protein transiently expressed on activated T cells, natural killer (NK) cells and immature dendritic cells that can be proteolytically cleaved by a metalloprotease and released to the extracellular milieu. The immunotherapeutic potential of LIGHT blockade was evaluated in vivo. Administration of an antagonist of LIGHT interaction with its receptors attenuated the course of graft-versus-host reaction and recapitulated the reduced cytotoxic activity of LIGHT-deficient T cells adoptively transferred into non-irradiated semiallogeneic recipients. The lack of LIGHT expression on donor T cells or blockade of LIGHT interaction with its receptors slowed down the rate of T cell proliferation and decreased the frequency of precursor alloreactive T cells, retarding T cell differentiation toward effector T cells. The blockade of LIGHT/LTβR/HVEM pathway was associated with delayed downregulation of interleukin-7Rα and delayed upregulation of inducible costimulatory molecule expression on donor alloreactive CD8 T cells that are typical features of impaired T cell differentiation. These results expose the relevance of LIGHT/LTβR/HVEM interaction for the potential therapeutic control of the allogeneic immune responses mediated by alloreactive CD8 T cells that can contribute to prolong allograft survival.
authors.affiliation: a Transplantation Immunobiology Section, Institute of Biomedicine, University of Leon and Castilla and Leon Regional Transplantation Coordination, Leon University Hospital , Leon , Spain.
authors.forename: Maria-Luisa
authors.initials: ML
authors.lastname: del Rio
authors.affiliation: a Transplantation Immunobiology Section, Institute of Biomedicine, University of Leon and Castilla and Leon Regional Transplantation Coordination, Leon University Hospital , Leon , Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernandez-Renedo
authors.affiliation: b CNRS UPR 3572, IBMC, Immunopathologie et Chimie Thérapeutique, 15 rue René Descartes , Strasbourg , France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Chaloin
authors.affiliation: c Institute of Medical Microbiology and Hospital Hygiene, University of Duesseldorf, Universitaetsstr. 1, Geb. 22.21 , Duesseldorf , D-40225 Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Scheu
authors.affiliation: c Institute of Medical Microbiology and Hospital Hygiene, University of Duesseldorf, Universitaetsstr. 1, Geb. 22.21 , Duesseldorf , D-40225 Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Pfeffer
authors.affiliation: d Department of International Affairs , Japan Science and Technology Agency, K´s Gobancho 7 , Gobancho Chiyoda-Ku , Tokyo , 102-0076 , Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Shintani
authors.affiliation: e Department of Hematology , University Hospital Virgen del Rocio / Institute of Biomedicine (IBIS / CSIC) , Sevilla , Spain.
authors.forename: Jose-Antonio
authors.initials: JA
authors.lastname: Perez-Simon
authors.affiliation: f Department of Biochemistry , University of Lausanne , 1066 Epalinges , Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Schneider
authors.affiliation: a Transplantation Immunobiology Section, Institute of Biomedicine, University of Leon and Castilla and Leon Regional Transplantation Coordination, Leon University Hospital , Leon , Spain.
authors.forename: Jose-Ignacio
authors.initials: JI
authors.lastname: Rodriguez-Barbosa
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D049109:Cell Proliferation; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D020395:Receptors, Interleukin-7 / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000235:genetics / Q000276:immunology*
chemical_list: D020395:Receptors, Interleukin-7; C505915:Tnfsf14 protein, mouse; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14
keywords: Alloreactivity; CD258); CD270); DcR3 (TNFRSF6b); HVEM (TNFRSF14; LIGHT (TNFSF14; LTβR (TNFRSF3); co-stimulation; cytotoxicity; graft rejection; graft-vs.-host disease; transplantation