Specific Dysregulation of IFNγ Production by Natural Killer Cells Confers Susceptibility to Viral Infection

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Cytomegalovirus (CMV) is a ubiquitous herpesvirus that largely infects the human population leading to a significant cause of disease and death in the immunocompromised and elderly. The study of CMV in animal models has helped understand the pathogenic consequences of CMV infection and adds substantial understanding of the complex interplay of host and virus in living systems. Natural Killer (NK) cells have emerged as an important player during CMV infection trough their specific recognition of viral particles determinants and subsequent secretion of cytokines and cytolytic granules. In the present study, we have generated different mouse models to specifically investigate quantify viral recognition and cytokine expression by NK cells during CMV infection as a measure of NK cell function. We found that even after proper recognition of infected cells by NK cells, the adequate production of IFNγ is crucial to restrain viral infection. Moreover, we demonstrated that IFNγ production by NK cells is genetically determined and directly linked to the IFNγ locus. Hence, we provide the first evidence for of a unique mechanism of IFNγ production by NK cells which regulates susceptibility to viral infection.

Vyšlo v časopise: Specific Dysregulation of IFNγ Production by Natural Killer Cells Confers Susceptibility to Viral Infection. PLoS Pathog 10(12): e32767. doi:10.1371/journal.ppat.1004511
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004511

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Zdroje

1. LanierLL (2005) NK cell recognition. Annu Rev Immunol 23: 225–274.

2. KarlhoferFM, RibaudoRK, YokoyamaWM (1992) MHC class I alloantigen specificity of Ly-49+ IL-2-activated natural killer cells. Nature 358: 66–70.

3. WagtmannN, BiassoniR, CantoniC, VerdianiS, MalnatiMS, et al. (1995) Molecular clones of the p58 NK cell receptor reveal immunoglobulin-related molecules with diversity in both the extra- and intracellular domains. Immunity 2: 439–449.

4. LanierLL (2008) Up on the tightrope: natural killer cell activation and inhibition. Nat Immunol 9: 495–502.

5. LiaoNS, BixM, ZijlstraM, JaenischR, RauletD (1991) MHC class I deficiency: susceptibility to natural killer (NK) cells and impaired NK activity. Science 253: 199–202.

6. FernandezNC, TreinerE, VanceRE, JamiesonAM, LemieuxS, et al. (2005) A subset of natural killer cells achieves self-tolerance without expressing inhibitory receptors specific for self-MHC molecules. Blood 105: 4416–4423.

7. AnfossiN, AndreP, GuiaS, FalkCS, RoetynckS, et al. (2006) Human NK cell education by inhibitory receptors for MHC class I. Immunity 25: 331–342.

8. YokoyamaWM, KimS (2006) Licensing of natural killer cells by self-major histocompatibility complex class I. Immunol Rev 214: 143–154.

9. KimS, Poursine-LaurentJ, TruscottSM, LybargerL, SongYJ, et al. (2005) Licensing of natural killer cells by host major histocompatibility complex class I molecules. Nature 436: 709–713.

10. VidalSM, LanierLL (2006) NK cell recognition of mouse cytomegalovirus-infected cells. Curr Top Microbiol Immunol 298: 183–206.

11. SjolinH, TomaselloE, Mousavi-JaziM, BartolazziA, KarreK, et al. (2002) Pivotal role of KARAP/DAP12 adaptor molecule in the natural killer cell-mediated resistance to murine cytomegalovirus infection. J Exp Med 195: 825–834.

12. Fodil-CornuN, LeeSH, BelangerS, MakrigiannisAP, BironCA, et al. (2008) Ly49h-deficient C57BL/6 mice: a new mouse cytomegalovirus-susceptible model remains resistant to unrelated pathogens controlled by the NK gene complex. J Immunol 181: 6394–6405.

13. LeeSH, ZaferA, de RepentignyY, KotharyR, TremblayML, et al. (2003) Transgenic expression of the activating natural killer receptor Ly49H confers resistance to cytomegalovirus in genetically susceptible mice. J Exp Med 197: 515–526.

14. FehnigerTA, CaiSF, CaoX, BredemeyerAJ, PrestiRM, et al. (2007) Acquisition of murine NK cell cytotoxicity requires the translation of a pre-existing pool of granzyme B and perforin mRNAs. Immunity 26: 798–811.

15. PrestiRM, PopkinDL, ConnickM, PaetzoldS, VirginHWt (2001) Novel cell type-specific antiviral mechanism of interferon gamma action in macrophages. J Exp Med 193: 483–496.

16. DavignonJL, CastanieP, YorkeJA, GautierN, ClementD, et al. (1996) Anti-human cytomegalovirus activity of cytokines produced by CD4+ T-cell clones specifically activated by IE1 peptides in vitro. J Virol 70: 2162–2169.

17. LohJ, ChuDT, O'GuinAK, YokoyamaWM, VirginHWt (2005) Natural killer cells utilize both perforin and gamma interferon to regulate murine cytomegalovirus infection in the spleen and liver. J Virol 79: 661–667.

18. SmithHR, ChuangHH, WangLL, SalcedoM, HeuselJW, et al. (2000) Nonstochastic coexpression of activation receptors on murine natural killer cells. J Exp Med 191: 1341–1354.

19. AraseH, MocarskiES, CampbellAE, HillAB, LanierLL (2002) Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors. Science 296: 1323–1326.

20. LeeSH, KimKS, Fodil-CornuN, VidalSM, BironCA (2009) Activating receptors promote NK cell expansion for maintenance, IL-10 production, and CD8 T cell regulation during viral infection. J Exp Med 206: 2235–2251.

21. OrangeJS, WangB, TerhorstC, BironCA (1995) Requirement for natural killer cell-produced interferon gamma in defense against murine cytomegalovirus infection and enhancement of this defense pathway by interleukin 12 administration. J Exp Med 182: 1045–1056.

22. JonckerNT, RauletDH (2008) Regulation of NK cell responsiveness to achieve self-tolerance and maximal responses to diseased target cells. Immunol Rev 224: 85–97.

23. KangHM, ZaitlenNA, WadeCM, KirbyA, HeckermanD, et al. (2008) Efficient control of population structure in model organism association mapping. Genetics 178: 1709–1723.

24. HengTS, PainterMW (2008) The Immunological Genome Project: networks of gene expression in immune cells. Nat Immunol 9: 1091–1094.

25. MabbottNA, BaillieJK, BrownH, FreemanTC, HumeDA (2013) An expression atlas of human primary cells: inference of gene function from coexpression networks. BMC Genomics 14: 632.

26. TassiI, CellaM, PrestiR, ColucciA, GilfillanS, et al. (2008) NK cell-activating receptors require PKC-theta for sustained signaling, transcriptional activation, and IFN-gamma secretion. Blood 112: 4109–4116.

27. TayCH, WelshRM (1997) Distinct organ-dependent mechanisms for the control of murine cytomegalovirus infection by natural killer cells. J Virol 71: 267–275.

28. BrutkiewiczRR, WelshRM (1995) Major histocompatibility complex class I antigens and the control of viral infections by natural killer cells. J Virol 69: 3967–3971.

29. OrrMT, MurphyWJ, LanierLL (2010) ‘Unlicensed’ natural killer cells dominate the response to cytomegalovirus infection. Nat Immunol 11: 321–327.

30. FangmannJ, SchwinzerR, WonigeitK (1991) Unusual phenotype of intestinal intraepithelial lymphocytes in the rat: predominance of T cell receptor alpha/beta+/CD2- cells and high expression of the RT6 alloantigen. Eur J Immunol 21: 753–760.

31. ChangS, AuneTM (2005) Histone hyperacetylated domains across the Ifng gene region in natural killer cells and T cells. Proc Natl Acad Sci U S A 102: 17095–17100.

32. BreamJH, HodgeDL, GonskyR, SpolskiR, LeonardWJ, et al. (2004) A distal region in the interferon-gamma gene is a site of epigenetic remodeling and transcriptional regulation by interleukin-2. J Biol Chem 279: 41249–41257.

33. ShiM, LinTH, AppellKC, BergLJ (2008) Janus-kinase-3-dependent signals induce chromatin remodeling at the Ifng locus during T helper 1 cell differentiation. Immunity 28: 763–773.

34. MiyakeT, SatohT, KatoH, MatsushitaK, KumagaiY, et al. (2010) IkappaBzeta is essential for natural killer cell activation in response to IL-12 and IL-18. Proc Natl Acad Sci U S A 107: 17680–17685.

35. JacobsenAB, TveitKM, PettersenEO, FossaSD, OusS (1991) Colony formation in urinary bladder carcinoma. Relationship to DNA flow cytometry, stage and histopathology. Anticancer Res 11: 777–781.

36. DjureticIM, LevanonD, NegreanuV, GronerY, RaoA, et al. (2007) Transcription factors T-bet and Runx3 cooperate to activate Ifng and silence Il4 in T helper type 1 cells. Nat Immunol 8: 145–153.

37. HattonRD, HarringtonLE, LutherRJ, WakefieldT, JanowskiKM, et al. (2006) A distal conserved sequence element controls Ifng gene expression by T cells and NK cells. Immunity 25: 717–729.

38. LeeDU, AvniO, ChenL, RaoA (2004) A distal enhancer in the interferon-gamma (IFN-gamma) locus revealed by genome sequence comparison. J Biol Chem 279: 4802–4810.

39. SchoenbornJR, DorschnerMO, SekimataM, SanterDM, ShnyrevaM, et al. (2007) Comprehensive epigenetic profiling identifies multiple distal regulatory elements directing transcription of the gene encoding interferon-gamma. Nat Immunol 8: 732–742.

40. ShnyrevaM, WeaverWM, BlanchetteM, TaylorSL, TompaM, et al. (2004) Evolutionarily conserved sequence elements that positively regulate IFN-gamma expression in T cells. Proc Natl Acad Sci U S A 101: 12622–12627.

41. WilsonCB, RowellE, SekimataM (2009) Epigenetic control of T-helper-cell differentiation. Nat Rev Immunol 9: 91–105.

42. CollinsPL, ChangS, HendersonM, SouttoM, DavisGM, et al. (2010) Distal regions of the human IFNG locus direct cell type-specific expression. J Immunol 185: 1492–1501.

43. CollinsPL, HendersonMA, AuneTM (2012) Diverse functions of distal regulatory elements at the IFNG locus. J Immunol 188: 1726–1733.

44. GomezJA, WapinskiOL, YangYW, BureauJF, GopinathS, et al. (2013) The NeST long ncRNA controls microbial susceptibility and epigenetic activation of the interferon-gamma locus. Cell 152: 743–754.

45. SchmolkaN, SerreK, GrossoAR, ReiM, PenningtonDJ, et al. (2013) Epigenetic and transcriptional signatures of stable versus plastic differentiation of proinflammatory gammadelta T cell subsets. Nat Immunol 14: 1093–1100.

46. HiraharaK, VahediG, GhoreschiK, YangXP, NakayamadaS, et al. (2011) Helper T-cell differentiation and plasticity: insights from epigenetics. Immunology 134: 235–245.

47. KoyanagiM, BaguetA, MartensJ, MargueronR, JenuweinT, et al. (2005) EZH2 and histone 3 trimethyl lysine 27 associated with Il4 and Il13 gene silencing in Th1 cells. J Biol Chem 280: 31470–31477.

48. ChangS, AuneTM (2007) Dynamic changes in histone-methylation ‘marks’ across the locus encoding interferon-gamma during the differentiation of T helper type 2 cells. Nat Immunol 8: 723–731.

49. FortinA, DiezE, RochefortD, LarocheL, MaloD, et al. (2001) Recombinant congenic strains derived from A/J and C57BL/6J: a tool for genetic dissection of complex traits. Genomics 74: 21–35.

50. DepatieC, MuiseE, LepageP, GrosP, VidalSM (1997) High-resolution linkage map in the proximity of the host resistance locus Cmv1. Genomics 39: 154–163.

51. TaiLH, GouletML, BelangerS, Toyama-SorimachiN, Fodil-CornuN, et al. (2008) Positive regulation of plasmacytoid dendritic cell function via Ly49Q recognition of class I MHC. J Exp Med 205: 3187–3199.

52. BoivinGA, PothlichetJ, SkameneE, BrownEG, Loredo-OstiJC, et al. (2012) Mapping of clinical and expression quantitative trait loci in a sex-dependent effect of host susceptibility to mouse-adapted influenza H3N2/HK/1/68. J Immunol 188: 3949–3960.

53. LanglaisD, CoutureC, BalsalobreA, DrouinJ (2012) The Stat3/GR interaction code: predictive value of direct/indirect DNA recruitment for transcription outcome. Mol Cell 47: 38–49.

54. ObergL, JohanssonS, MichaelssonJ, TomaselloE, VivierE, et al. (2004) Loss or mismatch of MHC class I is sufficient to trigger NK cell-mediated rejection of resting lymphocytes in vivo - role of KARAP/DAP12-dependent and -independent pathways. Eur J Immunol 34: 1646–1653.

55. ZhangX, ByrnesJK, GalTS, LiWH, BorevitzJO (2008) Whole genome transcriptome polymorphisms in Arabidopsis thaliana. Genome Biol 9: R165.