Blockade of Immunosuppressive Cytokines Restores NK Cell Antiviral Function in Chronic Hepatitis B Virus Infection

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NK cells are enriched in the liver, constituting around a third of intrahepatic lymphocytes. We have previously demonstrated that they upregulate the death ligand TRAIL in patients with chronic hepatitis B virus infection (CHB), allowing them to kill hepatocytes bearing TRAIL receptors. In this study we investigated whether, in addition to their pathogenic role, NK cells have antiviral potential in CHB. We characterised NK cell subsets and effector function in 64 patients with CHB compared to 31 healthy controls. We found that, in contrast to their upregulated TRAIL expression and maintenance of cytolytic function, NK cells had a markedly impaired capacity to produce IFN-γ in CHB. This functional dichotomy of NK cells could be recapitulated in vitro by exposure to the immunosuppressive cytokine IL-10, which was induced in patients with active CHB. IL-10 selectively suppressed NK cell IFN-γ production without altering cytotoxicity or death ligand expression. Potent antiviral therapy reduced TRAIL-expressing CD56^bright NK cells, consistent with the reduction in liver inflammation it induced; however, it was not able to normalise IL-10 levels or the capacity of NK cells to produce the antiviral cytokine IFN-γ. Blockade of IL-10 +/− TGF-β restored the capacity of NK cells from both the periphery and liver of patients with CHB to produce IFN-γ, thereby enhancing their non-cytolytic antiviral capacity. In conclusion, NK cells may be driven to a state of partial functional tolerance by the immunosuppressive cytokine environment in CHB. Their defective capacity to produce the antiviral cytokine IFN-γ persists in patients on antiviral therapy but can be corrected in vitro by IL-10+/− TGF-β blockade.

Vyšlo v časopise: Blockade of Immunosuppressive Cytokines Restores NK Cell Antiviral Function in Chronic Hepatitis B Virus Infection. PLoS Pathog 6(12): e32767. doi:10.1371/journal.ppat.1001227
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1001227

Souhrn

Zdroje

1. MainiMK

BoniC

LeeCK

LarrubiaJR

ReignatS

2000 The role of virus-specific CD8(+) cells in liver damage and viral control during persistent hepatitis B virus infection. J Exp Med 191 1269 1280

2. MainiMK

SchurichA

2010 The molecular basis of the failed immune response in chronic HBV: therapeutic implications. J Hepatol 52 616 619

3. DohertyDG

NorrisS

Madrigal-EstebasL

McEnteeG

TraynorO

1999 The human liver contains multiple populations of NK cells, T cells, and CD3+CD56+ natural T cells with distinct cytotoxic activities and Th1, Th2, and Th0 cytokine secretion patterns. J Immunol 163 2314 2321

4. DunnC

BrunettoM

ReynoldsG

ChristophidesT

KennedyPT

2007 Cytokines induced during chronic hepatitis B virus infection promote a pathway for NK cell-mediated liver damage. J Exp Med 204 667 680

5. CooperMA

FehnigerTA

CaligiuriMA

2001 The biology of human natural killer-cell subsets. Trends Immunol 22 633 640

6. VivierE

TomaselloE

BaratinM

WalzerT

UgoliniS

2008 Functions of natural killer cells. Nat Immunol 9 503 510

7. GuidottiLG

IshikawaT

HobbsMV

MatzkeB

SchreiberR

1996 Intracellular inactivation of the hepatitis B virus by cytotoxic T lymphocytes. Immunity 4 25 36

8. KakimiK

GuidottiLG

KoezukaY

ChisariFV

2000 Natural killer T cell activation inhibits hepatitis B virus replication in vivo. J Exp Med 192 921 930

9. TayCH

WelshRM

1997 Distinct organ-dependent mechanisms for the control of murine cytomegalovirus infection by natural killer cells. J Virol 71 267 275

10. AhlenstielG

TiterenceRH

KohC

EdlichB

FeldJJ

Natural killer cells are polarized toward cytotoxicity in chronic hepatitis C in an interferon-alfa-dependent manner. Gastroenterology 138 325 335 e321-322

11. StegmannKA

BjorkstromNK

VeberH

CiesekS

RieseP

1885 1897

12. TuZ

BozorgzadehA

PierceRH

KurtisJ

CrispeIN

2008 TLR-dependent cross talk between human Kupffer cells and NK cells. J Exp Med 205 233 244

13. KawakamiY

TomimoriY

YumotoK

HasegawaS

AndoT

2009 Inhibition of NK cell activity by IL-17 allows vaccinia virus to induce severe skin lesions in a mouse model of eczema vaccinatum. J Exp Med 206 1219 1225

14. CooperMA

FehnigerTA

TurnerSC

ChenKS

GhaheriBA

2001 Human natural killer cells: a unique innate immunoregulatory role for the CD56(bright) subset. Blood 97 3146 3151

15. FauriatC

LongEO

LjunggrenHG

Bryceson YT Regulation of human NK-cell cytokine and chemokine production by target cell recognition. Blood 115 2167 2176

16. DunnC

PeppaD

KhannaP

NebbiaG

JonesM

2009 Temporal analysis of early immune responses in patients with acute hepatitis B virus infection. Gastroenterology 137 1289 1300

17. AlterG

MartinMP

TeigenN

CarrWH

SuscovichTJ

2007 Differential natural killer cell-mediated inhibition of HIV-1 replication based on distinct KIR/HLA subtypes. J Exp Med 204 3027 3036

18. KhakooSI

ThioCL

MartinMP

BrooksCR

GaoX

2004 HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection. Science 305 872 874

19. CoudertJD

ZimmerJ

TomaselloE

CebecauerM

ColonnaM

2005 Altered NKG2D function in NK cells induced by chronic exposure to NKG2D ligand-expressing tumor cells. Blood 106 1711 1717

20. OppenheimDE

RobertsSJ

ClarkeSL

FillerR

LewisJM

2005 Sustained localized expression of ligand for the activating NKG2D receptor impairs natural cytotoxicity in vivo and reduces tumor immunosurveillance. Nat Immunol 6 928 937

21. SunJ

MadanR

KarpCL

BracialeTJ

2009 Effector T cells control lung inflammation during acute influenza virus infection by producing IL-10. Nat Med 15 277 284

22. WherryEJ

BlattmanJN

Murali-KrishnaK

Van Der MostR

AhmedR

2003 Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J Virol 77 4911 4927

23. ChenY

WeiH

SunR

DongZ

ZhangJ

2007 Increased susceptibility to liver injury in hepatitis B virus transgenic mice involves NKG2D-ligand interaction and natural killer cells. Hepatology 46 706 715

24. 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

25. ReefmanE

KayJG

WoodSM

OffenhauserC

BrownDL

Cytokine secretion is distinct from secretion of cytotoxic granules in NK cells J Immunol 184 4852 4862

26. CarauxA

KimN

BellSE

ZompiS

RansonT

2006 Phospholipase C-gamma2 is essential for NK cell cytotoxicity and innate immunity to malignant and virally infected cells. Blood 107 994 1002

27. KimN

SaudemontA

WebbL

CampsM

RuckleT

2007 The p110delta catalytic isoform of PI3K is a key player in NK-cell development and cytokine secretion. Blood 110 3202 3208

28. GuoH

SamarakoonA

VanhaesebroeckB

MalarkannanS

2008 The p110 delta of PI3K plays a critical role in NK cell terminal maturation and cytokine/chemokine generation. J Exp Med 205 2419 2435

29. MalarkannanS

RegunathanJ

ChuH

KutlesaS

ChenY

2007 Bcl10 plays a divergent role in NK cell-mediated cytotoxicity and cytokine generation. J Immunol 179 3752 3762

30. TrippCS

WolfSF

UnanueER

1993 Interleukin 12 and tumor necrosis factor alpha are costimulators of interferon gamma production by natural killer cells in severe combined immunodeficiency mice with listeriosis, and interleukin 10 is a physiologic antagonist. Proc Natl Acad Sci U S A 90 3725 3729

31. LassenMG

LukensJR

DolinaJS

BrownMG

Intrahepatic IL-10 maintains NKG2A+Ly49− liver NK cells in a functionally hyporesponsive state J Immunol 184 2693 2701

32. MaroofA

BeattieL

ZubairiS

SvenssonM

StagerS

2008 Posttranscriptional regulation of II10 gene expression allows natural killer cells to express immunoregulatory function. Immunity 29 295 305

33. BrockmanMA

KwonDS

TigheDP

PavlikDF

RosatoPC

2009 IL-10 is upregulated in multiple cell types during viremic HIV infection and reversibly inhibits virus-specific T cells. Blood 114 346 356

34. FlisiakR

Al-KadasiH

JaroszewiczJ

ProkopowiczD

FlisiakI

2004 Effect of lamivudine treatment on plasma levels of transforming growth factor beta1, tissue inhibitor of metalloproteinases-1 and metalloproteinase-1 in patients with chronic hepatitis B. World J Gastroenterol 10 2661 2665

35. YuJ

WeiM

BecknellB

TrottaR

LiuS

2006 Pro- and antiinflammatory cytokine signaling: reciprocal antagonism regulates interferon-gamma production by human natural killer cells. Immunity 24 575 590

36. BrooksDG

TrifiloMJ

EdelmannKH

TeytonL

McGavernDB

2006 Interleukin-10 determines viral clearance or persistence in vivo. Nat Med 12 1301 1309

37. EjrnaesM

FilippiCM

MartinicMM

LingEM

TogherLM

2006 Resolution of a chronic viral infection after interleukin-10 receptor blockade. J Exp Med 203 2461 2472

38. CheongJY

ChoSW

HwangIL

YoonSK

LeeJH

2006 Association between chronic hepatitis B virus infection and interleukin-10, tumor necrosis factor-alpha gene promoter polymorphisms. J Gastroenterol Hepatol 21 1163 1169

39. MiyazoeS

HamasakiK

NakataK

KajiyaY

KitajimaK

2002 Influence of interleukin-10 gene promoter polymorphisms on disease progression in patients chronically infected with hepatitis B virus. Am J Gastroenterol 97 2086 2092