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Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality.


ABSTRACT: Programmed death ligand-1 (PD-L1) interaction with PD-1 induces T cell exhaustion and is a therapeutic target to enhance immune responses against cancer and chronic infections. In murine bone marrow transplant models, PD-L1 expression on host target tissues reduces the incidence of graft-versus-host disease (GVHD). PD-L1 is also expressed on T cells; however, it is unclear whether PD-L1 on this population influences immune function. Here, we examined the effects of PD-L1 modulation of T cell function in GVHD. In patients with severe GVHD, PD-L1 expression was increased on donor T cells. Compared with mice that received WT T cells, GVHD was reduced in animals that received T cells from Pdl1-/- donors. PD-L1-deficient T cells had reduced expression of gut homing receptors, diminished production of inflammatory cytokines, and enhanced rates of apoptosis. Moreover, multiple bioenergetic pathways, including aerobic glycolysis, oxidative phosphorylation, and fatty acid metabolism, were also reduced in T cells lacking PD-L1. Finally, the reduction of acute GVHD lethality in mice that received Pdl1-/- donor cells did not affect graft-versus-leukemia responses. These data demonstrate that PD-L1 selectively enhances T cell-mediated immune responses, suggesting a context-dependent function of the PD-1/PD-L1 axis, and suggest selective inhibition of PD-L1 on donor T cells as a potential strategy to prevent or ameliorate GVHD.

SUBMITTER: Saha A 

PROVIDER: S-EPMC4922691 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality.

Saha Asim A   O'Connor Roddy S RS   Thangavelu Govindarajan G   Lovitch Scott B SB   Dandamudi Durga Bhavani DB   Wilson Caleph B CB   Vincent Benjamin G BG   Tkachev Victor V   Pawlicki Jan M JM   Furlan Scott N SN   Kean Leslie S LS   Aoyama Kazutoshi K   Taylor Patricia A PA   Panoskaltsis-Mortari Angela A   Foncea Rocio R   Ranganathan Parvathi P   Devine Steven M SM   Burrill Joel S JS   Guo Lili L   Sacristan Catarina C   Snyder Nathaniel W NW   Blair Ian A IA   Milone Michael C MC   Dustin Michael L ML   Riley James L JL   Bernlohr David A DA   Murphy William J WJ   Fife Brian T BT   Munn David H DH   Miller Jeffrey S JS   Serody Jonathan S JS   Freeman Gordon J GJ   Sharpe Arlene H AH   Turka Laurence A LA   Blazar Bruce R BR  

The Journal of clinical investigation 20160613 7


Programmed death ligand-1 (PD-L1) interaction with PD-1 induces T cell exhaustion and is a therapeutic target to enhance immune responses against cancer and chronic infections. In murine bone marrow transplant models, PD-L1 expression on host target tissues reduces the incidence of graft-versus-host disease (GVHD). PD-L1 is also expressed on T cells; however, it is unclear whether PD-L1 on this population influences immune function. Here, we examined the effects of PD-L1 modulation of T cell fun  ...[more]

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