title: Host programmed death ligand 1 is dominant over programmed death ligand 2 expression in regulating graft-versus-host disease lethality.
abstract: Programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, play an important role in the maintenance of peripheral tolerance. We explored the role of PD-1 ligands in regulating graft-versus-host disease (GVHD). Both PD-L1 and PD-L2 expression were upregulated in the spleen, liver, colon, and ileum of GVHD mice. Whereas PD-L2 expression was limited to hematopoietic cells, hematopoietic and endothelial cells expressed PD-L1. PD-1/PD-L1, but not PD-1/PD-L2, blockade markedly accelerated GVHD-induced lethality. Chimera studies suggest that PD-L1 expression on host parenchymal cells is more critical than hematopoietic cells in regulating acute GVHD. Rapid mortality onset in PD-L1-deficient hosts was associated with increased gut T-cell homing and loss of intestinal epithelial integrity, along with increased donor T-cell proliferation, activation, Th1 cytokine production, and reduced apoptosis. Bioenergetics profile analysis of proliferating alloreactive donor T-cells demonstrated increased aerobic glycolysis and oxidative phosphorylation in PD-L1-deficient hosts. Donor T-cells exhibited a hyperpolarized mitochondrial membrane potential, increased superoxide production, and increased expression of a glucose transporter in PD-L1-deficient hosts. Taken together, these data provide new insight into the differential roles of host PD-L1 and PD-L2 and their associated cellular and metabolic mechanisms controlling acute GVHD.
authors.affiliation: Masonic Cancer Center and Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN;
authors.forename: Asim
authors.initials: A
authors.lastname: Saha
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Aoyama
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Taylor
authors.forename: Brent H
authors.initials: BH
authors.lastname: Koehn
authors.forename: Rachelle G
authors.initials: RG
authors.lastname: Veenstra
authors.forename: Angela
authors.initials: A
authors.lastname: Panoskaltsis-Mortari
authors.forename: David H
authors.initials: DH
authors.lastname: Munn
authors.forename: William J
authors.initials: WJ
authors.lastname: Murphy
authors.forename: Miyuki
authors.initials: M
authors.lastname: Azuma
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Brian T
authors.initials: BT
authors.lastname: Fife
authors.forename: Mohammed H
authors.initials: MH
authors.lastname: Sayegh
authors.forename: Nader
authors.initials: N
authors.lastname: Najafian
authors.forename: Gerard
authors.initials: G
authors.lastname: Socie
authors.forename: Rafi
authors.initials: R
authors.lastname: Ahmed
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: Arlene H
authors.initials: AH
authors.lastname: Sharpe
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
mesh_terms: D000208:Acute Disease; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D060890:B7-H1 Antigen / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D005786:Gene Expression Regulation; D051246:Glucose Transport Proteins, Facilitative / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006019:Glycolysis; D006086:Graft vs Host Disease / Q000276:immunology / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000276:immunology / Q000473:pathology; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D010085:Oxidative Phosphorylation; D061166:Peripheral Tolerance / Q000276:immunology*; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016019:Survival Analysis; D023001:Transplantation Tolerance / Q000276:immunology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D051246:Glucose Transport Proteins, Facilitative; C491383:Pdcd1 protein, mouse; C556978:Pdcd1lg2 protein, mouse; C484279:Pdcd2 protein, mouse; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor
references.citation: Sci Transl Med. 2011 Nov 30;3(111):111ra120
references.pmid: 22133721
references.citation: J Immunol. 2001 May 15;166(10):5991-9
references.pmid: 11342614
references.citation: Am J Physiol Heart Circ Physiol. 2007 May;292(5):H2023-31
references.pmid: 17237240
references.citation: J Immunol. 2005 Mar 15;174(6):3408-15
references.pmid: 15749874
references.citation: Nat Rev Immunol. 2004 May;4(5):336-47
references.pmid: 15122199
references.citation: J Exp Med. 2001 Jun 4;193(11):1311-8
references.pmid: 11390438
references.citation: Blood. 2008 Mar 1;111(5):2909-18
references.pmid: 18057227
references.citation: Blood. 2012 Dec 6;120(24):4772-82
references.pmid: 22993390
references.citation: Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10691-6
references.pmid: 15249675
references.citation: Mol Cell Biol. 2005 Nov;25(21):9543-53
references.pmid: 16227604
references.citation: Blood. 2011 Jan 20;117(3):1030-41
references.pmid: 21063028
references.citation: Methods Mol Biol. 2009;554:165-81
references.pmid: 19513674
references.citation: Blood. 2009 Oct 1;114(14):3101-12
references.pmid: 19602708
references.citation: J Exp Med. 2009 Dec 21;206(13):3015-29
references.pmid: 20008522
references.citation: Am J Transplant. 2007 Dec;7(12):2683-92
references.pmid: 17924994
references.citation: Bone Marrow Transplant. 2006 Jun;37(12):1143-7
references.pmid: 16699531
references.citation: J Clin Invest. 2003 Feb;111(3):363-70
references.pmid: 12569162
references.citation: Blood. 2000 May 1;95(9):2754-9
references.pmid: 10779417
references.citation: J Immunol. 2001 Aug 1;167(3):1821-9
references.pmid: 11466408
references.citation: J Immunol. 2012 Jan 15;188(2):724-34
references.pmid: 22156590
references.citation: Blood. 2004 Feb 15;103(4):1542-7
references.pmid: 14563643
references.citation: Annu Rev Immunol. 2008;26:677-704
references.pmid: 18173375
references.citation: J Immunol. 2002 Nov 15;169(10):5538-45
references.pmid: 12421930
references.citation: Blood. 2009 Nov 12;114(20):4327-36
references.pmid: 19713461
references.citation: J Exp Med. 2006 Apr 17;203(4):883-95
references.pmid: 16606670
references.citation: J Neurosci Res. 2010 Jan;88(1):7-15
references.pmid: 19642196
references.citation: J Exp Med. 2001 Apr 2;193(7):839-46
references.pmid: 11283156
references.citation: J Clin Invest. 2010 Jul;120(7):2370-8
references.pmid: 20530875
references.citation: Blood. 2007 Aug 1;110(3):1064-72
references.pmid: 17449800
references.citation: J Leukoc Biol. 2008 Oct;84(4):949-57
references.pmid: 18577716
references.citation: J Exp Med. 2000 Oct 2;192(7):1027-34
references.pmid: 11015443
references.citation: J Clin Invest. 1999 Aug;104(4):459-67
references.pmid: 10449438
references.citation: Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13866-71
references.pmid: 11698646
references.citation: Int Immunol. 1994 Feb;6(2):263-75
references.pmid: 7512373
references.citation: J Clin Invest. 2010 Nov;120(11):3855-68
references.pmid: 20978352
references.citation: J Immunol. 2004 Feb 15;172(4):2530-41
references.pmid: 14764726
references.citation: J Exp Med. 2003 Jul 7;198(1):63-9
references.pmid: 12847137
references.citation: J Immunol. 1996 May 15;156(10):3727-36
references.pmid: 8621908
references.citation: Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3300-5
references.pmid: 19202076
references.citation: Transplantation. 2003 Sep 27;76(6):994-9
references.pmid: 14508368
references.citation: Immunity. 2004 Mar;20(3):327-36
references.pmid: 15030776
references.citation: Nat Immunol. 2001 Mar;2(3):261-8
references.pmid: 11224527
references.citation: Proc Natl Acad Sci U S A. 2008 Jul 8;105(27):9331-6
references.pmid: 18599457
references.citation: J Clin Invest. 2009 Mar;119(3):551-64
references.pmid: 19229109
references.citation: J Exp Med. 2001 Nov 19;194(10):1433-40
references.pmid: 11714750
references.citation: J Immunol. 2006 Feb 15;176(4):2238-48
references.pmid: 16455980
references.citation: Sci Transl Med. 2011 Jan 26;3(67):67ra8
references.pmid: 21270339
references.citation: J Immunol. 2003 Aug 1;171(3):1272-7
references.pmid: 12874215
references.citation: FEBS Lett. 2004 Sep 10;574(1-3):37-41
references.pmid: 15358536
references.citation: J Neuroimmunol. 2004 Oct;155(1-2):172-82
references.pmid: 15342209