RT Journal Article
T1 Immunotherapeutic targeting of LIGHT/LTβR/HVEM pathway fully recapitulates the reduced cytotoxic phenotype of LIGHT-deficient T cells.
A1 del Rio, Maria-Luisa
A1 Fernandez-Renedo, Carlos
A1 Chaloin, Olivier
A1 Scheu, Stefanie
A1 Pfeffer, Klaus
A1 Shintani, Yasushi
A1 Perez-Simon, Jose-Antonio
A1 Schneider, Pascal
A1 Rodriguez-Barbosa, Jose-Ignacio
K1 Alloreactivity
K1 CD258)
K1 CD270)
K1 DcR3 (TNFRSF6b)
K1 HVEM (TNFRSF14
K1 LIGHT (TNFSF14
K1 LTβR (TNFRSF3)
K1 co-stimulation
K1 cytotoxicity
K1 graft rejection
K1 graft-vs.-host disease
K1 transplantation
AB 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.
YR 2016
FD 2016-01-11
LK http://hdl.handle.net/10668/9722
UL http://hdl.handle.net/10668/9722
LA en
DS RISalud
RD Apr 11, 2025