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Title: Immunotherapeutic targeting of LIGHT/LTβR/HVEM pathway fully recapitulates the reduced cytotoxic phenotype of LIGHT-deficient T cells.
Authors: del Rio, Maria-Luisa
Fernandez-Renedo, Carlos
Chaloin, Olivier
Scheu, Stefanie
Pfeffer, Klaus
Shintani, Yasushi
Perez-Simon, Jose-Antonio
Schneider, Pascal
Rodriguez-Barbosa, Jose-Ignacio
Keywords: Alloreactivity;CD258);CD270);DcR3 (TNFRSF6b);HVEM (TNFRSF14;LIGHT (TNFSF14;LTβR (TNFRSF3);co-stimulation;cytotoxicity;graft rejection;graft-vs.-host disease;transplantation
metadata.dc.subject.mesh: Adoptive Transfer
CD8-Positive T-Lymphocytes
Cell Proliferation
Mice, Inbred BALB C
Mice, Knockout
Receptors, Interleukin-7
Signal Transduction
Tumor Necrosis Factor Ligand Superfamily Member 14
Issue Date: 11-Jan-2016
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.
metadata.dc.identifier.doi: 10.1080/19420862.2015.1132130
Appears in Collections:Producción 2020

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