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

Asim Saha, Roddy S. O'Connor, Govindarajan Thangavelu, Scott B. Lovitch, Durga Bhavani Dandamudi, Caleph B. Wilson, Benjamin G. Vincent, Victor Tkachev, Jan M. Pawlicki, Scott N. Furlan, Leslie S. Kean, Kazutoshi Aoyama, Patricia A. Taylor, Angela Panoskaltsis-Mortari, Rocio Foncea, Parvathi Ranganathan, Steven M. Devine, Joel S. Burrill, Lili Guo, Catarina Sacristan & 15 others Nathaniel W. Snyder, Ian A. Blair, Michael C. Milone, Michael L. Dustin, James L. Riley, David A. Bernlohr, William J. Murphy, Brian T. Fife, David H Munn, Jeffrey S. Miller, Jonathan S. Serody, Gordon J. Freeman, Arlene H. Sharpe, Laurence A. Turka, Bruce R. Blazar

Research output: Contribution to journalArticle

34 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2642-2660
Number of pages19
JournalJournal of Clinical Investigation
Volume126
Issue number7
DOIs
StatePublished - Jul 1 2016

Fingerprint

Graft vs Host Disease
Tissue Donors
Ligands
T-Lymphocytes
Transplants
Oxidative Phosphorylation
Glycolysis
Energy Metabolism
Leukemia
Fatty Acids
Bone Marrow
Apoptosis
Cytokines

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Saha, A., O'Connor, R. S., Thangavelu, G., Lovitch, S. B., Dandamudi, D. B., Wilson, C. B., ... Blazar, B. R. (2016). Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality. Journal of Clinical Investigation, 126(7), 2642-2660. https://doi.org/10.1172/JCI85796

Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality. / Saha, Asim; O'Connor, Roddy S.; Thangavelu, Govindarajan; Lovitch, Scott B.; Dandamudi, Durga Bhavani; Wilson, Caleph B.; Vincent, Benjamin G.; Tkachev, Victor; Pawlicki, Jan M.; Furlan, Scott N.; Kean, Leslie S.; Aoyama, Kazutoshi; Taylor, Patricia A.; Panoskaltsis-Mortari, Angela; Foncea, Rocio; Ranganathan, Parvathi; Devine, Steven M.; Burrill, Joel S.; Guo, Lili; Sacristan, Catarina; Snyder, Nathaniel W.; Blair, Ian A.; Milone, Michael C.; Dustin, Michael L.; Riley, James L.; Bernlohr, David A.; Murphy, William J.; Fife, Brian T.; Munn, David H; Miller, Jeffrey S.; Serody, Jonathan S.; Freeman, Gordon J.; Sharpe, Arlene H.; Turka, Laurence A.; Blazar, Bruce R.

In: Journal of Clinical Investigation, Vol. 126, No. 7, 01.07.2016, p. 2642-2660.

Research output: Contribution to journalArticle

Saha, A, O'Connor, RS, Thangavelu, G, Lovitch, SB, Dandamudi, DB, Wilson, CB, Vincent, BG, Tkachev, V, Pawlicki, JM, Furlan, SN, Kean, LS, Aoyama, K, Taylor, PA, Panoskaltsis-Mortari, A, Foncea, R, Ranganathan, P, Devine, SM, Burrill, JS, Guo, L, Sacristan, C, Snyder, NW, Blair, IA, Milone, MC, Dustin, ML, Riley, JL, Bernlohr, DA, Murphy, WJ, Fife, BT, Munn, DH, Miller, JS, Serody, JS, Freeman, GJ, Sharpe, AH, Turka, LA & Blazar, BR 2016, 'Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality', Journal of Clinical Investigation, vol. 126, no. 7, pp. 2642-2660. https://doi.org/10.1172/JCI85796
Saha A, O'Connor RS, Thangavelu G, Lovitch SB, Dandamudi DB, Wilson CB et al. Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality. Journal of Clinical Investigation. 2016 Jul 1;126(7):2642-2660. https://doi.org/10.1172/JCI85796
Saha, Asim ; O'Connor, Roddy S. ; Thangavelu, Govindarajan ; Lovitch, Scott B. ; Dandamudi, Durga Bhavani ; Wilson, Caleph B. ; Vincent, Benjamin G. ; Tkachev, Victor ; Pawlicki, Jan M. ; Furlan, Scott N. ; Kean, Leslie S. ; Aoyama, Kazutoshi ; Taylor, Patricia A. ; Panoskaltsis-Mortari, Angela ; Foncea, Rocio ; Ranganathan, Parvathi ; Devine, Steven M. ; Burrill, Joel S. ; Guo, Lili ; Sacristan, Catarina ; Snyder, Nathaniel W. ; Blair, Ian A. ; Milone, Michael C. ; Dustin, Michael L. ; Riley, James L. ; Bernlohr, David A. ; Murphy, William J. ; Fife, Brian T. ; Munn, David H ; Miller, Jeffrey S. ; Serody, Jonathan S. ; Freeman, Gordon J. ; Sharpe, Arlene H. ; Turka, Laurence A. ; Blazar, Bruce R. / Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality. In: Journal of Clinical Investigation. 2016 ; Vol. 126, No. 7. pp. 2642-2660.
@article{dfcab6d02c5945deaaccede75f0bc323,
title = "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.",
author = "Asim Saha and O'Connor, {Roddy S.} and Govindarajan Thangavelu and Lovitch, {Scott B.} and Dandamudi, {Durga Bhavani} and Wilson, {Caleph B.} and Vincent, {Benjamin G.} and Victor Tkachev and Pawlicki, {Jan M.} and Furlan, {Scott N.} and Kean, {Leslie S.} and Kazutoshi Aoyama and Taylor, {Patricia A.} and Angela Panoskaltsis-Mortari and Rocio Foncea and Parvathi Ranganathan and Devine, {Steven M.} and Burrill, {Joel S.} and Lili Guo and Catarina Sacristan and Snyder, {Nathaniel W.} and Blair, {Ian A.} and Milone, {Michael C.} and Dustin, {Michael L.} and Riley, {James L.} and Bernlohr, {David A.} and Murphy, {William J.} and Fife, {Brian T.} and Munn, {David H} and Miller, {Jeffrey S.} and Serody, {Jonathan S.} and Freeman, {Gordon J.} and Sharpe, {Arlene H.} and Turka, {Laurence A.} and Blazar, {Bruce R.}",
year = "2016",
month = "7",
day = "1",
doi = "10.1172/JCI85796",
language = "English (US)",
volume = "126",
pages = "2642--2660",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "7",

}

TY - JOUR

T1 - Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality

AU - Saha, Asim

AU - O'Connor, Roddy S.

AU - Thangavelu, Govindarajan

AU - Lovitch, Scott B.

AU - Dandamudi, Durga Bhavani

AU - Wilson, Caleph B.

AU - Vincent, Benjamin G.

AU - Tkachev, Victor

AU - Pawlicki, Jan M.

AU - Furlan, Scott N.

AU - Kean, Leslie S.

AU - Aoyama, Kazutoshi

AU - Taylor, Patricia A.

AU - Panoskaltsis-Mortari, Angela

AU - Foncea, Rocio

AU - Ranganathan, Parvathi

AU - Devine, Steven M.

AU - Burrill, Joel S.

AU - Guo, Lili

AU - Sacristan, Catarina

AU - Snyder, Nathaniel W.

AU - Blair, Ian A.

AU - Milone, Michael C.

AU - Dustin, Michael L.

AU - Riley, James L.

AU - Bernlohr, David A.

AU - Murphy, William J.

AU - Fife, Brian T.

AU - Munn, David H

AU - Miller, Jeffrey S.

AU - Serody, Jonathan S.

AU - Freeman, Gordon J.

AU - Sharpe, Arlene H.

AU - Turka, Laurence A.

AU - Blazar, Bruce R.

PY - 2016/7/1

Y1 - 2016/7/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84978399786&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84978399786&partnerID=8YFLogxK

U2 - 10.1172/JCI85796

DO - 10.1172/JCI85796

M3 - Article

VL - 126

SP - 2642

EP - 2660

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 7

ER -