Hepatitis C Virus (HCV) Evades NKG2D-Dependent NK Cell Responses through NS5A-Mediated Imbalance of Inflammatory Cytokines

English version České info

Understanding how hepatitis C virus (HCV) induces and circumvents the host's natural killer (NK) cell-mediated immunity is of critical importance in efforts to design effective therapeutics. We report here the decreased expression of the NKG2D activating receptor as a novel strategy adopted by HCV to evade NK-cell mediated responses. We show that chronic HCV infection is associated with expression of ligands for NKG2D, the MHC class I-related Chain (MIC) molecules, on hepatocytes. However, NKG2D expression is downmodulated on circulating NK cells, and consequently NK cell-mediated cytotoxic capacity and interferon-γ production are impaired. Using an endotoxin-free recombinant NS5A protein, we show that NS5A stimulation of monocytes through Toll-like Receptor 4 (TLR4) promotes p38- and PI3 kinase-dependent IL-10 production, while inhibiting IL-12 production. In turn, IL-10 triggers secretion of TGFβ which downmodulates NKG2D expression on NK cells, leading to their impaired effector functions. Moreover, culture supernatants of HCV JFH1 replicating Huh-7.5.1 cells reproduce the effect of recombinant NS5A on NKG2D downmodulation. Exogenous IL-15 can antagonize the TGFβ effect and restore normal NKG2D expression on NK cells. We conclude that NKG2D-dependent NK cell functions are modulated during chronic HCV infection, and demonstrate that this alteration can be prevented by exogenous IL-15, which could represent a meaningful adjuvant for therapeutic intervention.

Vyšlo v časopise: Hepatitis C Virus (HCV) Evades NKG2D-Dependent NK Cell Responses through NS5A-Mediated Imbalance of Inflammatory Cytokines. PLoS Pathog 6(11): e32767. doi:10.1371/journal.ppat.1001184
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1001184

Souhrn

Zdroje

1. RauletDH

2004

Interplay of natural killer cells and their receptors with the adaptive immune response.

Nat Immunol

996

1002

2. LanierLL

2005

NK cell recognition.

Annu Rev Immunol

225

274

3. NorrisS

CollinsC

DohertyDG

SmithF

McEnteeG

1998

Resident human hepatic lymphocytes are phenotypically different from circulating lymphocytes.

J Hepatol

4. KhakooSI

ThioCL

MartinMP

BrooksCR

GaoX

2004

HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection.

Science

305

872

874

5. Golden-MasonL

Madrigal-EstebasL

McGrathE

ConroyMJ

RyanEJ

2008

Altered natural killer cell subset distributions in resolved and persistent hepatitis C virus infection following single source exposure.

Gut

1121

1128

6. NattermannJ

FeldmannG

AhlenstielG

LanghansB

SauerbruchT

2006

Surface expression and cytolytic function of natural killer cell receptors is altered in chronic hepatitis C.

Gut

869

877

7. De MariaA

FogliM

MazzaS

BassoM

PicciottoA

2007

Increased natural cytotoxicity receptor expression and relevant IL-10 production in NK cells from chronically infected viremic HCV patients.

Eur J Immunol

445

455

8. AhlenstielG

TiterenceRH

KohC

EdlichB

FeldJJ

2009

Natural Killer Cells Are Polarized Toward Cytotoxicity in Chronic Hepatitis C in an Interferon-Alfa-Dependent Manner.

Gastroenterology

9. BonorinoP

RamzanM

CamousX

Dufeu-DuchesneT

TheluMA

2009

Fine characterization of intrahepatic NK cells expressing natural killer receptors in chronic hepatitis B and C.

J Hepatol

458

467

10. OlivieroB

VarchettaS

PaudiceE

MicheloneG

ZaramellaM

2009

Natural killer cell functional dichotomy in chronic hepatitis B and chronic hepatitis C virus infections.

Gastroenterology

137

1151–1160, 1160 e1151

1157

11. KottililS

YanMY

ReitanoKN

ZhangX

LempickiR

2009

Human immunodeficiency virus and hepatitis C infections induce distinct immunologic imprints in peripheral mononuclear cells.

Hepatology

12. BauerS

GrohV

WuJ

SteinleA

PhillipsJH

1999

Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA.

Science

285

727

729

13. GrohV

WuJ

YeeC

SpiesT

2002

Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation.

Nature

419

734

738

14. LodoenM

OgasawaraK

HamermanJA

AraseH

HouchinsJP

2003

NKG2D-mediated natural killer cell protection against cytomegalovirus is impaired by viral gp40 modulation of retinoic acid early inducible 1 gene molecules.

J Exp Med

197

1245

1253

15. RolleA

Mousavi-JaziM

ErikssonM

OdebergJ

Soderberg-NauclerC

2003

Effects of human cytomegalovirus infection on ligands for the activating NKG2D receptor of NK cells: up-regulation of UL16-binding protein (ULBP)1 and ULBP2 is counteracted by the viral UL16 protein.

J Immunol

171

902

908

16. Stern-GinossarN

ElefantN

ZimmermannA

WolfDG

SalehN

2007

Host immune system gene targeting by a viral miRNA.

Science

317

376

381

17. KrmpoticA

HasanM

LoewendorfA

SauligT

HaleniusA

2005

NK cell activation through the NKG2D ligand MULT-1 is selectively prevented by the glycoprotein encoded by mouse cytomegalovirus gene m145.

J Exp Med

201

211

220

18. GrohV

RhinehartR

Randolph-HabeckerJ

ToppMS

RiddellSR

2001

Costimulation of CD8alphabeta T cells by NKG2D via engagement by MIC induced on virus-infected cells.

Nat Immunol

255

260

19. TiengV

2002

Binding of Escherichia coli adhesin AfaE to CD55 triggers cell-surface expression of the MHC class I-related molecule MICA.

Proc Natl Acad Sci USA

2977

2982

20. DannSM

WangHC

GambarinKJ

ActorJK

RobinsonP

2005

Interleukin-15 activates human natural killer cells to clear the intestinal protozoan cryptosporidium.

J Infect Dis

192

1294

1302

21. LeeJC

LeeKM

KimDW

HeoDS

2004

Elevated TGF-beta1 secretion and down-modulation of NKG2D underlies impaired NK cytotoxicity in cancer patients.

J Immunol

172

7335

7340

22. FrieseMA

WischhusenJ

WickW

WeilerM

EiseleG

2004

RNA interference targeting transforming growth factor-beta enhances NKG2D-mediated antiglioma immune response, inhibits glioma cell migration and invasiveness, and abrogates tumorigenicity in vivo.

Cancer Res

7596

7603

23. CastriconiR

CantoniC

Della ChiesaM

VitaleM

MarcenaroE

2003

Transforming growth factor beta 1 inhibits expression of NKp30 and NKG2D receptors: consequences for the NK-mediated killing of dendritic cells.

Proc Natl Acad Sci U S A

100

4120

4125

24. CrottaS

RonconiV

UlivieriC

BaldariCT

ValianteNM

2006

Cytoskeleton rearrangement induced by tetraspanin engagement modulates the activation of T and NK cells.

Eur J Immunol

919

929

25. DattaA

Sinha-DattaU

DhillonNK

BuchS

NicotC

2006

The HTLV-I p30 interferes with TLR4 signaling and modulates the release of pro- and anti-inflammatory cytokines from human macrophages.

J Biol Chem

281

23414

23424

26. StocklJ

VetrH

MajdicO

ZlabingerG

KuechlerE

1999

Human major group rhinoviruses downmodulate the accessory function of monocytes by inducing IL-10.

J Clin Invest

104

957

965

27. BiebackK

LienE

KlaggeIM

AvotaE

Schneider-SchauliesJ

2002

Hemagglutinin protein of wild-type measles virus activates toll-like receptor 2 signaling.

J Virol

8729

8736

28. AkiraS

TakedaK

2004

Toll-like receptor signalling.

Nature Reviews Immunology

499

511

29. MaW

LimW

GeeK

AucoinS

NandanD

2001

The p38 mitogen-activated kinase pathway regulates the human interleukin-10 promoter via the activation of Sp1 transcription factor in lipopolysaccharide-stimulated human macrophages.

J Biol Chem

276

13664

13674

30. FukaoT

TanabeM

TerauchiY

OtaT

MatsudaS

2002

PI3K-mediated negative feedback regulation of IL-12 production in DCs.

Nat Immunol

875

881

31. ZhongJ

GastaminzaP

ChungJ

StamatakiZ

IsogawaM

2006

Persistent hepatitis C virus infection in vitro: coevolution of virus and host.

J Virol

11082

11093

32. WaltersKA

SyderAJ

LedererSL

DiamondDL

PaeperB

2009

Genomic analysis reveals a potential role for cell cycle perturbation in HCV-mediated apoptosis of cultured hepatocytes.

PLoS Pathog

e1000269

33. EbiharaT

ShingaiM

MatsumotoM

WakitaT

SeyaT

2008

Hepatitis C virus-infected hepatocytes extrinsically modulate dendritic cell maturation to activate T cells and natural killer cells.

Hepatology

34. WakitaT

PietschmannT

KatoT

DateT

MiyamotoM

2005

Production of infectious hepatitis C virus in tissue culture from a cloned viral genome.

Nat Med

791

796

35. ZhongJ

GastaminzaP

ChengG

KapadiaS

KatoT

2005

Robust hepatitis C virus infection in vitro.

Proc Natl Acad Sci U S A

102

9294

9299

36. DeignanT

CurryMP

DohertyDG

Golden-MasonL

VolkovY

2002

Decrease in hepatic CD56(+) T cells and V alpha 24(+) natural killer T cells in chronic hepatitis C viral infection.

J Hepatol

101

108

37. YamagiwaS

MatsudaY

IchidaT

HondaY

TakamuraM

2008

Sustained response to interferon-alpha plus ribavirin therapy for chronic hepatitis C is closely associated with increased dynamism of intrahepatic natural killer and natural killer T cells.

Hepatol Res

664

672

38. VermijlenD

SeynaeveC

LuoD

KruhofferM

EizirikDL

2004

High-density oligonucleotide array analysis reveals extensive differences between freshly isolated blood and hepatic natural killer cells.

Eur J Immunol

2529

2540

39. KennedyPT

GehringAJ

NowbathA

SeldenC

QuagliaA

2008

The expression and function of NKG2D molecule on intrahepatic CD8+ T cells in chronic viral hepatitis.

J Viral Hepat

901

909

40. MeresseB

ChenZ

CiszewskiC

TretiakovaM

BhagatG

2004

Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease.

Immunity

357

366

41. LucasPJ

KimSJ

MackallCL

TelfordWG

ChuYW

2006

Dysregulation of IL-15-mediated T-cell homeostasis in TGF-beta dominant-negative receptor transgenic mice.

Blood

108

2789

2795

42. YuJ

WeiM

BecknellB

TrottaR

LiuS

2006

Pro- and antiinflammatory cytokine signaling: reciprocal antagonism regulates interferon-gamma production by human natural killer cells.

Immunity

575

590

43. BenahmedM

MeresseB

ArnulfB

BarbeU

MentionJJ

2007

Inhibition of TGF-beta signaling by IL-15: a new role for IL-15 in the loss of immune homeostasis in celiac disease.

Gastroenterology

132

994

1008

44. SandauMM

SchlunsKS

LefrancoisL

JamesonSC

2004

Cutting edge: transpresentation of IL-15 by bone marrow-derived cells necessitates expression of IL-15 and IL-15R alpha by the same cells.

J Immunol

173

6537

6541

45. GaleMJr

FoyEM

2005

Evasion of intracellular host defence by hepatitis C virus.

Nature

436

939

945

46. Golden-MasonL

RosenHR

2006

Natural killer cells: primary target for hepatitis C virus immune evasion strategies?

Liver Transpl

363

372

47. CoradoJ

ToroF

RiveraH

BiancoNE

DeibisL

1997

Impairment of natural killer (NK) cytotoxic activity in hepatitis C virus (HCV) infection.

Clin Exp Immunol

109

451

457

48. MeierUC

OwenRE

TaylorE

WorthA

NaoumovN

2005

Shared alterations in NK cell frequency, phenotype, and function in chronic human immunodeficiency virus and hepatitis C virus infections.

J Virol

12365

12374

49. ParG

RukavinaD

PodackER

HoranyiM

Szekeres-BarthoJ

2002

Decrease in CD3-negative-CD8dim(+) and Vdelta2/Vgamma9 TcR+ peripheral blood lymphocyte counts, low perforin expression and the impairment of natural killer cell activity is associated with chronic hepatitis C virus infection.

J Hepatol

514

522

50. MorishimaC

PaschalDM

WangCC

YoshiharaCS

WoodBL

2006

Decreased NK cell frequency in chronic hepatitis C does not affect ex vivo cytolytic killing.

Hepatology

573

580

51. ConrySJ

MilkovichKA

YonkersNL

RodriguezB

BernsteinHB

2009

Impaired plasmacytoid dendritic cell (PDC)-NK cell activity in viremic human immunodeficiency virus infection attributable to impairments in both PDC and NK cell function.

J Virol

11175

11187

52. BrycesonYT

MarchME

BarberDF

LjunggrenHG

LongEO

2005

Cytolytic granule polarization and degranulation controlled by different receptors in resting NK cells.

J Exp Med

202

1001

1012

53. CerboniC

NeriF

CasartelliN

ZingoniA

CosmanD

2007

Human immunodeficiency virus 1 Nef protein downmodulates the ligands of the activating receptor NKG2D and inhibits natural killer cell-mediated cytotoxicity.

J Gen Virol

242

250

54. ThomasM

BonameJM

FieldS

NejentsevS

SalioM

2008

Down-regulation of NKG2D and NKp80 ligands by Kaposi's sarcoma-associated herpesvirus K5 protects against NK cell cytotoxicity.

Proc Natl Acad Sci U S A

105

1656

1661

55. KinjyoI

InoueH

HamanoS

FukuyamaS

YoshimuraT

2006

Loss of SOCS3 in T helper cells resulted in reduced immune responses and hyperproduction of interleukin 10 and transforming growth factor-beta 1.

J Exp Med

203

1021

1031

56. BradyMT

MacDonaldAJ

RowanAG

MillsKH

2003

Hepatitis C virus non-structural protein 4 suppresses Th1 responses by stimulating IL-10 production from monocytes.

Eur J Immunol

3448

3457

57. DolganiucA

KodysK

KopaszA

MarshallC

DoT

2003

Hepatitis C virus core and nonstructural protein 3 proteins induce pro- and anti-inflammatory cytokines and inhibit dendritic cell differentiation.

J Immunol

170

5615

5624

58. ChangS

DolganiucA

SzaboG

2007

Toll-like receptors 1 and 6 are involved in TLR2-mediated macrophage activation by hepatitis C virus core and NS3 proteins.

J Leukoc Biol

479

487

59. LiH

HanY

GuoQ

ZhangM

CaoX

2009

Cancer-expanded myeloid-derived suppressor cells induce anergy of NK cells through membrane-bound TGF-beta 1.

J Immunol

182

240

249

60. HoechstB

OrmandyLA

BallmaierM

LehnerF

KrugerC

2008

A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4(+)CD25(+)Foxp3(+) T cells.

Gastroenterology

135

234

243

61. HoechstB

VoigtlaenderT

OrmandyL

GamrekelashviliJ

ZhaoF

2009

Myeloid derived suppressor cells inhibit natural killer cells in patients with hepatocellular carcinoma via the NKp30 receptor.

Hepatology

799

807

62. GeeK

AngelJB

MishraS

BlahoianuMA

KumarA

2007

IL-10 regulation by HIV-Tat in primary human monocytic cells: involvement of calmodulin/calmodulin-dependent protein kinase-activated p38 MAPK and Sp-1 and CREB-1 transcription factors.

J Immunol

178

798

807

63. LambertSL

MartinezOM

2007

Latent membrane protein 1 of EBV activates phosphatidylinositol 3-kinase to induce production of IL-10.

J Immunol

179

8225

8234

64. MaloneyG

SchroderM

BowieAG

2005

Vaccinia virus protein A52R activates p38 mitogen-activated protein kinase and potentiates lipopolysaccharide-induced interleukin-10.

J Biol Chem

280

30838

30844

65. AbelM

SeneD

PolS

BourliereM

PoynardT

2006

Intrahepatic virus-specific IL-10-producing CD8 T cells prevent liver damage during chronic hepatitis C virus infection.

Hepatology

1607

1616

66. WaltersKA

JoyceMA

ThompsonJC

SmithMW

YehMM

2006

Host-specific response to HCV infection in the chimeric SCID-beige/Alb-uPA mouse model: role of the innate antiviral immune response.

PLoS Pathog

e59

67. Golden-MasonL

KellyAM

DohertyDG

TraynorO

McEnteeG

2004

Hepatic interleuklin 15 (IL-15) expression: implications for local NK/NKT cell homeostasis and development.

Clin Exp Immunol

138

101

68. Golden-MasonL

KlarquistJ

WahedAS

RosenHR

2008

Cutting edge: programmed death-1 expression is increased on immunocytes in chronic hepatitis C virus and predicts failure of response to antiviral therapy: race-dependent differences.

J Immunol

180

3637

3641

69. MortierE

QuemenerA

VusioP

LorenzenI

BoublikY

2006

Soluble interleukin-15 receptor alpha (IL-15R alpha)-sushi as a selective and potent agonist of IL-15 action through IL-15R beta/gamma. Hyperagonist IL-15 x IL-15R alpha fusion proteins.

J Biol Chem

281

1612

1619

70. HorngT

BezbradicaJS

MedzhitovR

2007

NKG2D signaling is coupled to the interleukin 15 receptor signaling pathway.

Nat Immunol

1345

1352

71. JinushiM

TakeharaT

TatsumiT

KantoT

GrohV

2003

Autocrine/paracrine IL-15 that is required for type I IFN-mediated dendritic cell expression of MHC class I-related chain A and B is impaired in hepatitis C virus infection.

J Immunol

171

5423

5429

72. BonorinoP

LeroyV

Dufeu-DuchesneT

Tongiani-DashanS

SturmN

2007

Features and distribution of CD8 T cells with human leukocyte antigen class I-specific receptor expression in chronic hepatitis C.

Hepatology