Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality.
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.
Asim
A
Saha
Roddy S
RS
O'Connor
Govindarajan
G
Thangavelu
Scott B
SB
Lovitch
Durga Bhavani
DB
Dandamudi
Caleph B
CB
Wilson
Benjamin G
BG
Vincent
Victor
V
Tkachev
Jan M
JM
Pawlicki
Scott N
SN
Furlan
Leslie S
LS
Kean
Kazutoshi
K
Aoyama
Patricia A
PA
Taylor
Angela
A
Panoskaltsis-Mortari
Rocio
R
Foncea
Parvathi
P
Ranganathan
Steven M
SM
Devine
Joel S
JS
Burrill
Lili
L
Guo
Catarina
C
Sacristan
Nathaniel W
NW
Snyder
Ian A
IA
Blair
Michael C
MC
Milone
Michael L
ML
Dustin
James L
JL
Riley
David A
DA
Bernlohr
William J
WJ
Murphy
Brian T
BT
Fife
David H
DH
Munn
Jeffrey S
JS
Miller
Jonathan S
JS
Serody
Gordon J
GJ
Freeman
Arlene H
AH
Sharpe
Laurence A
LA
Turka
Bruce R
BR
Blazar
D000818:Animals; D017209:Apoptosis; D060890:B7-H1 Antigen / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000166:cytology; D016026:Bone Marrow Transplantation; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000276:immunology; D005973:Glutamine / Q000378:metabolism; D006019:Glycolysis; D006086:Graft vs Host Disease / Q000276:immunology*; D006801:Humans; D007249:Inflammation; D007963:Leukocytes, Mononuclear / Q000166:cytology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010100:Oxygen; D010766:Phosphorylation; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D016896:Treatment Outcome
D060890:B7-H1 Antigen; C423236:CD274 protein, human; C498919:Cd274 protein, mouse; D016207:Cytokines; C105992:PDCD1 protein, human; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D005973:Glutamine; D005947:Glucose; D010100:Oxygen