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Respiratory Syncytial Virus Interferon Antagonist NS1 Protein Suppresses and Skews the Human T Lymphocyte Response


We recently demonstrated that the respiratory syncytial virus (RSV) NS1 protein, an antagonist of host type I interferon (IFN-I) production and signaling, has a suppressive effect on the maturation of human dendritic cells (DC) that was only partly dependent on released IFN-I. Here we investigated whether NS1 affects the ability of DC to activate CD8+ and CD4+ T cells. Human DC were infected with RSV deletion mutants lacking the NS1 and/or NS2 genes and assayed for the ability to activate autologous T cells in vitro, which were analyzed by multi-color flow cytometry. Deletion of the NS1, but not NS2, protein resulted in three major effects: (i) an increased activation and proliferation of CD8+ T cells that express CD103, a tissue homing integrin that directs CD8+ T cells to mucosal epithelial cells of the respiratory tract and triggers cytolytic activity; (ii) an increased activation and proliferation of Th17 cells, which have recently been shown to have anti-viral effects and also indirectly attract neutrophils; and (iii) decreased activation of IL-4-producing CD4+ T cells - which are associated with enhanced RSV disease - and reduced proliferation of total CD4+ T cells. Except for total CD4+ T cell proliferation, none of the T cell effects appeared to be due to increased IFN-I signaling. In the infected DC, deletion of the NS1 and NS2 genes strongly up-regulated the expression of cytokines and other molecules involved in DC maturation. This was partly IFN-I-independent, and thus might account for the T cell effects. Taken together, these data demonstrate that the NS1 protein suppresses proliferation and activation of two of the protective cell populations (CD103+ CD8+ T cells and Th17 cells), and promotes proliferation and activation of Th2 cells that can enhance RSV disease.


Vyšlo v časopise: Respiratory Syncytial Virus Interferon Antagonist NS1 Protein Suppresses and Skews the Human T Lymphocyte Response. PLoS Pathog 7(4): e32767. doi:10.1371/journal.ppat.1001336
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1001336

Souhrn

We recently demonstrated that the respiratory syncytial virus (RSV) NS1 protein, an antagonist of host type I interferon (IFN-I) production and signaling, has a suppressive effect on the maturation of human dendritic cells (DC) that was only partly dependent on released IFN-I. Here we investigated whether NS1 affects the ability of DC to activate CD8+ and CD4+ T cells. Human DC were infected with RSV deletion mutants lacking the NS1 and/or NS2 genes and assayed for the ability to activate autologous T cells in vitro, which were analyzed by multi-color flow cytometry. Deletion of the NS1, but not NS2, protein resulted in three major effects: (i) an increased activation and proliferation of CD8+ T cells that express CD103, a tissue homing integrin that directs CD8+ T cells to mucosal epithelial cells of the respiratory tract and triggers cytolytic activity; (ii) an increased activation and proliferation of Th17 cells, which have recently been shown to have anti-viral effects and also indirectly attract neutrophils; and (iii) decreased activation of IL-4-producing CD4+ T cells - which are associated with enhanced RSV disease - and reduced proliferation of total CD4+ T cells. Except for total CD4+ T cell proliferation, none of the T cell effects appeared to be due to increased IFN-I signaling. In the infected DC, deletion of the NS1 and NS2 genes strongly up-regulated the expression of cytokines and other molecules involved in DC maturation. This was partly IFN-I-independent, and thus might account for the T cell effects. Taken together, these data demonstrate that the NS1 protein suppresses proliferation and activation of two of the protective cell populations (CD103+ CD8+ T cells and Th17 cells), and promotes proliferation and activation of Th2 cells that can enhance RSV disease.


Zdroje

1. Garcia-SastreA

EgorovA

MatassovD

BrandtS

LevyDE

1998 Influenza A virus lacking the NS1 gene replicates in interferon-deficient systems. Virology 252 324 330

2. WeberF

HallerO

2007 Viral suppression of the interferon system. Biochimie 89 836 842

3. ToughDF

2004 Type I interferon as a link between innate and adaptive immunity through dendritic cell stimulation. Leuk Lymphoma 45 257 264

4. FujitaH

AsahinaA

TadaY

FujiwaraH

TamakiK

2005 Type I interferons inhibit maturation and activation of mouse Langerhans cells. J Invest Dermatol 125 126 133

5. von HoegenP

ZawatzkyR

SchirrmacherV

1990 Modification of tumor cells by a low dose of Newcastle disease virus. III. Potentiation of tumor-specific cytolytic T cell activity via induction of interferon-alpha/beta. Cell Immunol 126 80 90

6. ThompsonLJ

KolumamGA

ThomasS

Murali-KrishnaK

2006 Innate inflammatory signals induced by various pathogens differentially dictate the IFN-I dependence of CD8 T cells for clonal expansion and memory formation. J Immunol 177 1746 1754

7. KolumamGA

ThomasS

ThompsonLJ

SprentJ

Murali-KrishnaK

2005 Type I interferons act directly on CD8 T cells to allow clonal expansion and memory formation in response to viral infection. J Exp Med 202 637 650

8. Havenar-DaughtonC

KolumamGA

Murali-KrishnaK

2006 Cutting Edge: The direct action of type I IFN on CD4 T cells is critical for sustaining clonal expansion in response to a viral but not a bacterial infection. J Immunol 176 3315 3319

9. ToughDF

BorrowP

SprentJ

1996 Induction of bystander T cell proliferation by viruses and type I interferon in vivo. Science 272 1947 1950

10. GallagherKM

LauderS

ReesIW

GallimoreAM

GodkinAJ

2009 Type I interferon (IFN alpha) acts directly on human memory CD4+ T cells altering their response to antigen. J Immunol 183 2915 2920

11. LachgarA

BizziniB

1994 Involvement of alpha-interferon in HIV-1 induced immunosuppression. A potential target for AIDS prophylaxis and treatment. Biomed Pharmacother 48 73 77

12. EricksonS

MatikainenS

ThyrellL

SangfeltO

JulkunenI

2002 Interferon-alpha inhibits Stat5 DNA-binding in IL-2 stimulated primary T-lymphocytes. Eur J Biochem 269 29 37

13. SchmidlinH

DontjeW

GrootF

LigthartSJ

ColantonioAD

2006 Stimulated plasmacytoid dendritic cells impair human T-cell development. Blood 108 3792 3800

14. ZaguryD

LachgarA

ChamsV

FallLS

BernardJ

1998 Interferon alpha and Tat involvement in the immunosuppression of uninfected T cells and C-C chemokine decline in AIDS. Proc Natl Acad Sci U S A 95 3851 3856

15. ChiB

DickensheetsHL

SpannKM

AlstonMA

LuongoC

2006 Alpha and lambda interferon together mediate suppression of CD4 T cells induced by respiratory syncytial virus. J Virol 80 5032 5040

16. CollinsPL

CroweJEJ

2007 Respiratory Syncytial Virus and Metapneumovirus.

KnipeDM

HowleyPM

GriffinDE

LambRA

Martin MA etal

Fields Virology. 5 ed Philadelphia Lippincott-Raven Publishers 1601 1646

17. CollinsPL

GrahamBS

2008 Viral and host factors in human respiratory syncytial virus pathogenesis. J Virol 82 2040 2055

18. HallCB

WalshEE

LongCE

SchnabelKC

1991 Immunity to and frequency of reinfection with respiratory syncytial virus. J Infect Dis 163 693 698

19. HendersonFW

CollierAM

ClydeWAJr

DennyFW

1979 Respiratory-syncytial-virus infections, reinfections and immunity. A prospective, longitudinal study in young children. N Engl J Med 300 530 534

20. BukreyevA

YangL

FrickeJ

ChengL

WardJM

2008 The secreted form of respiratory syncytial virus G glycoprotein helps the virus evade antibody-mediated restriction of replication by acting as an antigen decoy and through effects on Fc receptor-bearing leukocytes. J Virol 82 12191 12204

21. BossertB

MarozinS

ConzelmannKK

2003 Nonstructural proteins NS1 and NS2 of bovine respiratory syncytial virus block activation of interferon regulatory factor 3. J Virol 77 8661 8668

22. ElliottJ

LynchOT

SuessmuthY

QianP

BoydCR

2007 Respiratory syncytial virus NS1 protein degrades STAT2 by using the Elongin-Cullin E3 ligase. J Virol 81 3428 3436

23. LoMS

BrazasRM

HoltzmanMJ

2005 Respiratory syncytial virus nonstructural proteins NS1 and NS2 mediate inhibition of Stat2 expression and alpha/beta interferon responsiveness. J Virol 79 9315 9319

24. SpannKM

TranKC

ChiB

RabinRL

CollinsPL

2004 Suppression of the induction of alpha, beta, and lambda interferons by the NS1 and NS2 proteins of human respiratory syncytial virus in human epithelial cells and macrophages [corrected]. J Virol 78 4363 4369

25. SpannKM

TranKC

CollinsPL

2005 Effects of nonstructural proteins NS1 and NS2 of human respiratory syncytial virus on interferon regulatory factor 3, NF-kappaB, and proinflammatory cytokines. J Virol 79 5353 5362

26. LingZ

TranKC

TengMN

2009 Human respiratory syncytial virus nonstructural protein NS2 antagonizes the activation of beta interferon transcription by interacting with RIG-I. J Virol 83 3734 3742

27. BitkoV

ShulyayevaO

MazumderB

MusiyenkoA

RamaswamyM

2007 Nonstructural Proteins of Respiratory Syncytial Virus Suppress Premature Apoptosis by an NF-{kappa}B-Dependent, Interferon-Independent Mechanism and Facilitate Virus Growth. J Virol 81 1786 1795

28. MunirS

Le NouenC

LuongoC

BuchholzUJ

CollinsPL

2008 Nonstructural proteins 1 and 2 of respiratory syncytial virus suppress maturation of human dendritic cells. J Virol 82 8780 8796

29. VarolC

LandsmanL

FoggDK

GreenshteinL

GildorB

2007 Monocytes give rise to mucosal, but not splenic, conventional dendritic cells. J Exp Med 204 171 180

30. de BreeGJ

van LeeuwenEM

OutTA

JansenHM

JonkersRE

2005 Selective accumulation of differentiated CD8+ T cells specific for respiratory viruses in the human lung. J Exp Med 202 1433 1442

31. XuY

ZhanY

LewAM

NaikSH

KershawMH

2007 Differential development of murine dendritic cells by GM-CSF versus Flt3 ligand has implications for inflammation and trafficking. J Immunol 179 7577 7584

32. FarrarJD

SmithJD

MurphyTL

LeungS

StarkGR

2000 Selective loss of type I interferon-induced STAT4 activation caused by a minisatellite insertion in mouse Stat2. Nat Immunol 1 65 69

33. RoggeL

D'AmbrosioD

BiffiM

PennaG

MinettiLJ

1998 The role of Stat4 in species-specific regulation of Th cell development by type I IFNs. J Immunol 161 6567 6574

34. Le Floc'hA

JalilA

VergnonI

Le Maux ChansacB

LazarV

2007 Alpha E beta 7 integrin interaction with E-cadherin promotes antitumor CTL activity by triggering lytic granule polarization and exocytosis. J Exp Med 204 559 570

35. RihsS

WalkerC

VirchowJCJr

BoerC

KroegelC

1996 Differential expression of alpha E beta 7 integrins on bronchoalveolar lavage T lymphocyte subsets: regulation by alpha 4 beta 1-integrin crosslinking and TGF-beta. Am J Respir Cell Mol Biol 15 600 610

36. CepekKL

ShawSK

ParkerCM

RussellGJ

MorrowJS

1994 Adhesion between epithelial cells and T lymphocytes mediated by E-cadherin and the alpha E beta 7 integrin. Nature 372 190 193

37. FranciszkiewiczK

Le Floc'hA

JalilA

VigantF

RobertT

2009 Intratumoral induction of CD103 triggers tumor-specific CTL function and CCR5-dependent T-cell retention. Cancer Res 69 6249 6255

38. BettsMR

BrenchleyJM

PriceDA

De RosaSC

DouekDC

2003 Sensitive and viable identification of antigen-specific CD8+ T cells by a flow cytometric assay for degranulation. J Immunol Methods 281 65 78

39. SederRA

DarrahPA

RoedererM

2008 T-cell quality in memory and protection: implications for vaccine design. Nat Rev Immunol 8 247 258

40. WongP

PamerEG

2003 Feedback regulation of pathogen-specific T cell priming. Immunity 18 499 511

41. FukudaM

1991 Lysosomal membrane glycoproteins. Structure, biosynthesis, and intracellular trafficking. J Biol Chem 266 21327 21330

42. Abu-KhabarKS

ArmstrongJA

HoM

1992 Type I interferons (IFN-alpha and -beta) suppress cytotoxin (tumor necrosis factor-alpha and lymphotoxin) production by mitogen-stimulated human peripheral blood mononuclear cell. J Leukoc Biol 52 165 172

43. LiuAN

MohammedAZ

RiceWR

FiedeldeyDT

LiebermannJS

1999 Perforin-independent CD8(+) T-cell-mediated cytotoxicity of alveolar epithelial cells is preferentially mediated by tumor necrosis factor-alpha: relative insensitivity to Fas ligand. Am J Respir Cell Mol Biol 20 849 858

44. RatnerA

ClarkWR

1993 Role of TNF-alpha in CD8+ cytotoxic T lymphocyte-mediated lysis. J Immunol 150 4303 4314

45. SinghA

SureshM

2007 A role for TNF in limiting the duration of CTL effector phase and magnitude of CD8 T cell memory. J Leukoc Biol 82 1201 1211

46. FiresteinGS

RoederWD

LaxerJA

TownsendKS

WeaverCT

1989 A new murine CD4+ T cell subset with an unrestricted cytokine profile. J Immunol 143 518 525

47. HegazyAN

PeineM

HelmstetterC

PanseI

FrohlichA

2010 Interferons direct Th2 cell reprogramming to generate a stable GATA-3(+)T-bet(+) cell subset with combined Th2 and Th1 cell functions. Immunity 32 116 128

48. ZhuJ

PaulWE

2010 CD4(+) T Cell Plasticity-Th2 Cells Join the Crowd. Immunity 32 11 13

49. BukreyevA

BelyakovIM

PrinceGA

YimKC

HarrisKK

2005 Expression of interleukin-4 by recombinant respiratory syncytial virus is associated with accelerated inflammation and a nonfunctional cytotoxic T-lymphocyte response following primary infection but not following challenge with wild-type virus. J Virol 79 9515 9526

50. van der VeldenVH

LaanMP

BaertMR

de Waal MalefytR

NeijensHJ

2001 Selective development of a strong Th2 cytokine profile in high-risk children who develop atopy: risk factors and regulatory role of IFN-gamma, IL-4 and IL-10. Clin Exp Allergy 31 997 1006

51. AnnunziatoF

CosmiL

SantarlasciV

MaggiL

LiottaF

2007 Phenotypic and functional features of human Th17 cells. J Exp Med 204 1849 1861

52. MarijanovicZ

RagimbeauJ

van der HeydenJ

UzeG

PellegriniS

2007 Comparable potency of IFNalpha2 and IFNbeta on immediate JAK/STAT activation but differential down-regulation of IFNAR2. Biochem J 407 141 151

53. IzaguirreA

BarnesBJ

AmruteS

YeowWS

MegjugoracN

2003 Comparative analysis of IRF and IFN-alpha expression in human plasmacytoid and monocyte-derived dendritic cells. J Leukoc Biol 74 1125 1138

54. GrahamBS

BuntonLA

WrightPF

KarzonDT

1991 Role of T lymphocyte subsets in the pathogenesis of primary infection and rechallenge with respiratory syncytial virus in mice. J Clin Invest 88 1026 1033

55. FishautM

TubergenD

McIntoshK

1980 Cellular response to respiratory viruses with particular reference to children with disorders of cell-mediated immunity. J Pediatr 96 179 186

56. WoodberryT

SuscovichTJ

HenryLM

AugustM

WaringMT

2005 Alpha E beta 7 (CD103) expression identifies a highly active, tonsil-resident effector-memory CTL population. J Immunol 175 4355 4362

57. SmythLJ

KirbyJA

CunninghamAC

2007 Role of the mucosal integrin alpha(E)(CD103)beta(7) in tissue-restricted cytotoxicity. Clin Exp Immunol 149 162 170

58. O'QuinnDB

PalmerMT

LeeYK

WeaverCT

2008 Emergence of the Th17 pathway and its role in host defense. Adv Immunol 99 115 163

59. KollsJK

LindenA

2004 Interleukin-17 family members and inflammation. Immunity 21 467 476

60. WiehlerS

ProudD

2007 Interleukin-17A modulates human airway epithelial responses to human rhinovirus infection. Am J Physiol Lung Cell Mol Physiol 293 L505 515

61. FujisawaH

2008 Neutrophils play an essential role in cooperation with antibody in both protection against and recovery from pulmonary infection with influenza virus in mice. J Virol 82 2772 2783

62. SporriR

JollerN

HilbiH

OxeniusA

2008 A novel role for neutrophils as critical activators of NK cells. J Immunol 181 7121 7130

63. PepperM

LinehanJL

PaganAJ

ZellT

DileepanT

2010 Different routes of bacterial infection induce long-lived TH1 memory cells and short-lived TH17 cells. Nat Immunol 11 83 89

64. KohyamaS

OhnoS

IsodaA

MoriyaO

BelladonnaML

2007 IL-23 enhances host defense against vaccinia virus infection via a mechanism partly involving IL-17. J Immunol 179 3917 3925

65. McKinstryKK

StruttTM

BuckA

CurtisJD

DibbleJP

2009 IL-10 deficiency unleashes an influenza-specific Th17 response and enhances survival against high-dose challenge. J Immunol 182 7353 7363

66. BeckerY

2006 Respiratory syncytial virus (RSV) evades the human adaptive immune system by skewing the Th1/Th2 cytokine balance toward increased levels of Th2 cytokines and IgE, markers of allergy–a review. Virus Genes 33 235 252

67. MiyairiI

DeVincenzoJP

2008 Human genetic factors and respiratory syncytial virus disease severity. Clin Microbiol Rev 21 686 703

68. ChoiEH

LeeHJ

YooT

ChanockSJ

2002 A common haplotype of interleukin-4 gene IL4 is associated with severe respiratory syncytial virus disease in Korean children. J Infect Dis 186 1207 1211

69. HoebeeB

RietveldE

BontL

OostenM

HodemaekersHM

2003 Association of severe respiratory syncytial virus bronchiolitis with interleukin-4 and interleukin-4 receptor alpha polymorphisms. J Infect Dis 187 2 11

70. ErmersMJ

HoebeeB

HodemaekersHM

KimmanTG

KimpenJL

2007 IL-13 genetic polymorphism identifies children with late wheezing after respiratory syncytial virus infection. J Allergy Clin Immunol 119 1086 1091

71. FortonJT

RowlandsK

RockettK

HanchardN

HerbertM

2009 Genetic association study for RSV bronchiolitis in infancy at the 5q31 cytokine cluster. Thorax 64 345 352

72. ZhangW

YangH

KongX

MohapatraS

San Juan-VergaraH

2005 Inhibition of respiratory syncytial virus infection with intranasal siRNA nanoparticles targeting the viral NS1 gene. Nat Med 11 56 62

73. ParronchiP

De CarliM

ManettiR

SimonelliC

SampognaroS

1992 IL-4 and IFN (alpha and gamma) exert opposite regulatory effects on the development of cytolytic potential by Th1 or Th2 human T cell clones. J Immunol 149 2977 2983

74. BrinkmannV

GeigerT

AlkanS

HeusserCH

1993 Interferon alpha increases the frequency of interferon gamma-producing human CD4+ T cells. J Exp Med 178 1655 1663

75. LopezCB

Garcia-SastreA

WilliamsBR

MoranTM

2003 Type I interferon induction pathway, but not released interferon, participates in the maturation of dendritic cells induced by negative-strand RNA viruses. J Infect Dis 187 1126 1136

76. BerghallH

SirenJ

SarkarD

JulkunenI

FisherPB

2006 The interferon-inducible RNA helicase, mda-5, is involved in measles virus-induced expression of antiviral cytokines. Microbes Infect 8 2138 2144

77. PadovanE

SpagnoliGC

FerrantiniM

HebererM

2002 IFN-alpha2a induces IP-10/CXCL10 and MIG/CXCL9 production in monocyte-derived dendritic cells and enhances their capacity to attract and stimulate CD8+ effector T cells. J Leukoc Biol 71 669 676

78. WuestT

AustinBA

UematsuS

ThapaM

AkiraS

2006 Intact TRL 9 and type I interferon signaling pathways are required to augment HSV-1 induced corneal CXCL9 and CXCL10. J Neuroimmunol 179 46 52

79. KaikoGE

HorvatJC

BeagleyKW

HansbroPM

2008 Immunological decision-making: how does the immune system decide to mount a helper T-cell response? Immunology 123 326 338

80. BettelliE

KornT

OukkaM

KuchrooVK

2008 Induction and effector functions of T(H)17 cells. Nature 453 1051 1057

81. McRaeBL

SemnaniRT

HayesMP

van SeventerGA

1998 Type I IFNs inhibit human dendritic cell IL-12 production and Th1 cell development. J Immunol 160 4298 4304

82. RuddBD

LukerGD

LukerKE

PeeblesRS

LukacsNW

2007 Type I interferon regulates respiratory virus infected dendritic cell maturation and cytokine production. Viral Immunol 20 531 540

83. HussellT

BaldwinCJ

O'GarraA

OpenshawPJ

1997 CD8+ T cells control Th2-driven pathology during pulmonary respiratory syncytial virus infection. Eur J Immunol 27 3341 3349

84. SrikiatkhachornA

BracialeTJ

1997 Virus-specific CD8+ T lymphocytes downregulate T helper cell type 2 cytokine secretion and pulmonary eosinophilia during experimental murine respiratory syncytial virus infection. J Exp Med 186 421 432

85. CulleyFJ

PollottJ

OpenshawPJ

2002 Age at first viral infection determines the pattern of T cell-mediated disease during reinfection in adulthood. J Exp Med 196 1381 1386

86. Le NouenC

HillyerP

MunirS

WinterCC

McCartyT

2010 Effects of human respiratory syncytial virus, metapneumovirus, parainfluenza virus 3 and influenza virus on CD4+ T cell activation by dendritic cells. PLoS One 5 e15017

87. MurphyBR

SotnikovAV

LawrenceLA

BanksSM

PrinceGA

1990 Enhanced pulmonary histopathology is observed in cotton rats immunized with formalin-inactivated respiratory syncytial virus (RSV) or purified F glycoprotein and challenged with RSV 3-6 months after immunization. Vaccine 8 497 502

88. SchuurhuisDH

FuN

OssendorpF

MeliefCJ

2006 Ins and outs of dendritic cells. Int Arch Allergy Immunol 140 53 72

89. Le NouenC

HillyerP

MunirS

WinterCC

McCartyT

2010 Effects of human respiratory syncytial virus, metapneumovirus, parainfluenza virus 3 and influenza virus on CD4+ T cell activation by dendritic cells. PLoS One 5 e15017

90. JaksE

GavutisM

UzeG

MartalJ

PiehlerJ

2007 Differential receptor subunit affinities of type I interferons govern differential signal activation. J Mol Biol 366 525 539

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