title: Lack of PD-L1 expression by iNKT cells improves the course of influenza A infection.
abstract: There is evidence indicating that invariant Natural Killer T (iNKT) cells play an important role in defense against influenza A virus (IAV). However, the effect of inhibitory receptor, programmed death-1 (PD-1), and its ligands, programmed death ligand (PD-L) 1 and 2 on iNKT cells in protection against IAV remains to be elucidated. Here we investigated the effects of these co-stimulatory molecules on iNKT cells in the response to influenza. We discovered that compare to the wild type, PD-L1 deficient mice show reduced sensitivity to IAV infection as evident by reduced weight loss, decreased pulmonary inflammation and cellular infiltration. In contrast, PD-L2 deficient mice showed augmented weight loss, pulmonary inflammation and cellular infiltration compare to the wild type mice after influenza infection. Adoptive transfer of iNKT cells from wild type, PD-L1 or PD-L2 deficient mice into iNKT cell deficient mice recapitulated these findings. Interestingly, in our transfer system PD-L1(-/-)-derived iNKT cells produced high levels of interferon-gamma whereas PD-L2(-/-)-derived iNKT cells produced high amounts of interleukin-4 and 13 suggesting a role for these cytokines in sensitivity to influenza. We identified that PD-L1 negatively regulates the frequency of iNKT cell subsets in the lungs of IAV infected mice. Altogether, these results demonstrate that lack of PD-L1 expression by iNKT cells reduces the sensitivity to IAV and that the presence of PD-L2 is important for dampening the deleterious inflammatory responses after IAV infection. Our findings potentially have clinical implications for developing new therapies for influenza.
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Hadi
authors.initials: H
authors.lastname: Maazi
authors.forename: Abinav K
authors.initials: AK
authors.lastname: Singh
authors.forename: Anneliese O
authors.initials: AO
authors.lastname: Speak
authors.forename: Vincent
authors.initials: V
authors.lastname: Lombardi
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lam
authors.forename: Bryant
authors.initials: B
authors.lastname: Khoo
authors.forename: Kyung Soo
authors.initials: KS
authors.lastname: Inn
authors.forename: Arlene H
authors.initials: AH
authors.lastname: Sharpe
authors.forename: Jae U
authors.initials: JU
authors.lastname: Jung
authors.forename: Omid
authors.initials: O
authors.lastname: Akbari
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000172:deficiency* / Q000235:genetics*; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000821:virology; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D055786:Gene Knockout Techniques; D053118:Influenza A Virus, H1N1 Subtype / Q000502:physiology*; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D055611:Natural Killer T-Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism* / Q000821:virology*; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000378:metabolism; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000172:deficiency / Q000235:genetics
chemical_list: D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D016207:Cytokines; C556978:Pdcd1lg2 protein, mouse; D061027:Programmed Cell Death 1 Ligand 2 Protein
references.citation: Nat Immunol. 2011 May 29;12(7):631-8
references.pmid: 21623379
references.citation: PLoS Pathog. 2010 Oct 07;6(10):e1001139
references.pmid: 20949022
references.citation: Eur J Immunol. 2008 Apr;38(4):1012-23
references.pmid: 18350544
references.citation: J Immunol. 1998 Jun 15;160(12):6032-8
references.pmid: 9637519
references.citation: J Exp Med. 2011 Apr 11;208(4):729-45
references.pmid: 21444661
references.citation: J Clin Invest. 2012 Aug;122(8):2967-82
references.pmid: 22797302
references.citation: Nat Med. 1999 Dec;5(12):1365-9
references.pmid: 10581077
references.citation: J Immunol. 2011 Aug 1;187(3):1097-105
references.pmid: 21697456
references.citation: Eur J Immunol. 2006 Jan;36(1):58-64
references.pmid: 16358363
references.citation: Nat Rev Immunol. 2007 Dec;7(12):929-41
references.pmid: 18037897
references.citation: J Allergy Clin Immunol. 2013 Apr;131(4):1048-57, 1057.e1-2
references.pmid: 23174661
references.citation: J Immunol. 2011 May 15;186(10):5590-602
references.pmid: 21490153
references.citation: J Virol. 1996 Aug;70(8):5230-5
references.pmid: 8764032
references.citation: Proc Natl Acad Sci U S A. 2006 Aug 1;103(31):11695-700
references.pmid: 16864790
references.citation: J Immunol. 1997 Mar 1;158(5):2363-74
references.pmid: 9036986
references.citation: Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11287-92
references.pmid: 18685112
references.citation: J Immunol. 2010 Feb 15;184(4):2107-15
references.pmid: 20083656
references.citation: J Exp Med. 2005 Jul 18;202(2):231-7
references.pmid: 16027236
references.citation: Eur J Immunol. 2003 Nov;33(11):3117-26
references.pmid: 14579280
references.citation: J Immunol. 2002 Nov 15;169(10):5538-45
references.pmid: 12421930
references.citation: Proc Natl Acad Sci U S A. 2000 Apr 11;97(8):4309-14
references.pmid: 10725408
references.citation: J Exp Med. 2006 Apr 17;203(4):883-95
references.pmid: 16606670
references.citation: J Virol. 1998 Nov;72(11):8550-8
references.pmid: 9765393
references.citation: J Infect Dis. 2006 Nov 1;194 Suppl 2:S82-91
references.pmid: 17163394
references.citation: Immunol Cell Biol. 2007 Feb-Mar;85(2):85-92
references.pmid: 17213831
references.citation: J Clin Invest. 2002 Jun;109(11):1471-9
references.pmid: 12045261
references.citation: J Exp Med. 2004 Jun 21;199(12):1619-30
references.pmid: 15210741
references.citation: Vaccine. 2008 Dec 9;26(52):6965-74
references.pmid: 18848593
references.citation: J Immunol. 2007 Mar 1;178(5):2714-20
references.pmid: 17312113
references.citation: Eur J Immunol. 2008 Jul;38(7):1913-22
references.pmid: 18521958
references.citation: J Exp Med. 2002 Apr 1;195(7):869-79
references.pmid: 11927631
references.citation: Annu Rev Immunol. 2007;25:297-336
references.pmid: 17150027
references.citation: Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4275-80
references.pmid: 20160101
references.citation: J Immunol. 2004 Aug 1;173(3):2159-66
references.pmid: 15265953
references.citation: Mucosal Immunol. 2010 Jan;3(1):81-91
references.pmid: 19741598
references.citation: Nat Rev Immunol. 2009 Jan;9(1):28-38
references.pmid: 19079136
references.citation: J Exp Med. 2000 Oct 2;192(7):1027-34
references.pmid: 11015443
references.citation: J Infect Dis. 1973 Oct;128(4):488-93
references.pmid: 4743545
references.citation: J Clin Microbiol. 1986 Jul;24(1):157-60
references.pmid: 3722363
references.citation: Science. 1997 Nov 28;278(5343):1623-6
references.pmid: 9374462
references.citation: Trends Immunol. 2006 Apr;27(4):183-7
references.pmid: 16527542
references.citation: Trends Immunol. 2007 Nov;28(11):491-6
references.pmid: 17964217
references.citation: Microcirculation. 2002 Apr;9(2):133-45
references.pmid: 11932780
references.citation: J Clin Invest. 2004 Nov;114(10):1379-88
references.pmid: 15545985
references.citation: J Immunol. 2004 Feb 15;172(4):2530-41
references.pmid: 14764726
references.citation: J Immunol. 2003 Feb 1;170(3):1430-4
references.pmid: 12538704
references.citation: J Virol. 2003 Sep;77(18):10168-71
references.pmid: 12941930
references.citation: Allergy. 2011 Feb;66(2):155-62
references.pmid: 20722638
references.citation: Immunology. 2011 May;133(1):29-40
references.pmid: 21303364
references.citation: J Clin Invest. 2008 Dec;118(12):4036-48
references.pmid: 19033672
references.citation: J Clin Microbiol. 1986 Jan;23(1):66-72
references.pmid: 3700610
references.citation: Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10691-6
references.pmid: 15249675
references.citation: J Virol. 2002 May;76(9):4294-303
references.pmid: 11932395
references.citation: J Immunol. 2005 May 1;174(9):5332-40
references.pmid: 15843530
references.citation: Expert Opin Ther Targets. 2009 Feb;13(2):153-62
references.pmid: 19236234
references.citation: Arch Intern Med. 1982 Jan;142(1):85-9
references.pmid: 7053739
references.citation: Immunol Cell Biol. 2004 Jun;82(3):332-41
references.pmid: 15186265
references.citation: J Exp Med. 2000 Oct 2;192(7):921-30
references.pmid: 11015434
references.citation: J Clin Invest. 2011 Jan;121(1):57-69
references.pmid: 21157038
references.citation: J Exp Med. 2011 Jan 17;208(1):167-80
references.pmid: 21187318
references.citation: Am J Epidemiol. 1980 Dec;112(6):798-811
references.pmid: 7457471
references.citation: Nat Med. 2003 May;9(5):582-8
references.pmid: 12669034