Human Cytomegalovirus Drives Epigenetic Imprinting of the Locus in NKG2C Natural Killer Cells


Upon viral infection, the innate interferon (IFN)-γ producing Natural Killer (NK) cells provide fast, but short-term protection, while adaptive T cells confer delayed, but long-lasting immunity. Once acquired, effector properties remain stably imprinted in the T cell memory progeny. Recently, it was shown that human cytomegalovirus (HCMV) infection can shape the human NK cell repertoire and drive the generation and maintenance of NK cell expansions, which express the activating receptor CD94/NKG2C and have been described as memory-like NK cells. However, the molecular mechanisms underlying NK cell adaptive properties driven by HCMV infection have not been completely defined. In this study, we identify epigenetic imprinting of the IFNG locus as selective hallmark and crucial mechanism driving strong and stable IFN-γ expression in HCMV-specific NK cell expansions, thus providing a molecular basis for the regulation of adaptive features in innate cells.


Vyšlo v časopise: Human Cytomegalovirus Drives Epigenetic Imprinting of the Locus in NKG2C Natural Killer Cells. PLoS Pathog 10(10): e32767. doi:10.1371/journal.ppat.1004441
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004441

Souhrn

Upon viral infection, the innate interferon (IFN)-γ producing Natural Killer (NK) cells provide fast, but short-term protection, while adaptive T cells confer delayed, but long-lasting immunity. Once acquired, effector properties remain stably imprinted in the T cell memory progeny. Recently, it was shown that human cytomegalovirus (HCMV) infection can shape the human NK cell repertoire and drive the generation and maintenance of NK cell expansions, which express the activating receptor CD94/NKG2C and have been described as memory-like NK cells. However, the molecular mechanisms underlying NK cell adaptive properties driven by HCMV infection have not been completely defined. In this study, we identify epigenetic imprinting of the IFNG locus as selective hallmark and crucial mechanism driving strong and stable IFN-γ expression in HCMV-specific NK cell expansions, thus providing a molecular basis for the regulation of adaptive features in innate cells.


Zdroje

1. StetsonDB, MohrsM, ReinhardtRL, BaronJL, WangZE, et al. (2003) Constitutive cytokine mRNAs mark natural killer (NK) and NK T cells poised for rapid effector function. J Exp Med 198: 1069–1076.

2. MurphyKM, ReinerSL (2002) The lineage decisions of helper T cells. Nat Rev Immunol 2: 933–944.

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

4. BalasubramaniA, MukasaR, HattonRD, WeaverCT (2010) Regulation of the Ifng locus in the context of T-lineage specification and plasticity. Immunol Rev 238: 216–232.

5. 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.

6. 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.

7. MacianF (2005) NFAT proteins: key regulators of T-cell development and function. Nat Rev Immunol 5: 472–484.

8. 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.

9. DongJ, ChangHD, IvascuC, QianY, RezaiS, et al. (2013) Loss of methylation at the IFNG promoter and CNS-1 is associated with the development of functional IFN-gamma memory in human CD4(+) T lymphocytes. Eur J Immunol 43: 793–804.

10. FitzpatrickDR, ShirleyKM, McDonaldLE, Bielefeldt-OhmannH, KayGF, et al. (1998) Distinct methylation of the interferon gamma (IFN-gamma) and interleukin 3 (IL-3) genes in newly activated primary CD8+ T lymphocytes: regional IFN-gamma promoter demethylation and mRNA expression are heritable in CD44(high)CD8+ T cells. J Exp Med 188: 103–117.

11. 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.

12. TatoCM, MartinsGA, HighFA, DiCioccioCB, ReinerSL, et al. (2004) Cutting Edge: Innate production of IFN-gamma by NK cells is independent of epigenetic modification of the IFN-gamma promoter. J Immunol 173: 1514–1517.

13. 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.

14. Luetke-EverslohM, CicekBB, SiracusaF, ThomJT, HamannA, et al. (2014) NK cells gain higher IFN-gamma competence during terminal differentiation. Eur J Immunol 44: 2074–2084.

15. RolleA, PollmannJ, CerwenkaA (2013) Memory of infections: an emerging role for natural killer cells. PLoS Pathog 9: e1003548.

16. SunJC, BeilkeJN, LanierLL (2009) Adaptive immune features of natural killer cells. Nature 457: 557–561.

17. O'LearyJG, GoodarziM, DraytonDL, von AndrianUH (2006) T cell- and B cell-independent adaptive immunity mediated by natural killer cells. Nat Immunol 7: 507–516.

18. CooperMA, ElliottJM, KeyelPA, YangL, CarreroJA, et al. (2009) Cytokine-induced memory-like natural killer cells. Proc Natl Acad Sci U S A 106: 1915–1919.

19. RomeeR, SchneiderSE, LeongJW, ChaseJM, KeppelCR, et al. (2012) Cytokine activation induces human memory-like NK cells. Blood 120: 4751–4760.

20. NiJ, MillerM, StojanovicA, GarbiN, CerwenkaA (2012) Sustained effector function of IL-12/15/18-preactivated NK cells against established tumors. J Exp Med 209: 2351–2365.

21. DokunAO, KimS, SmithHR, KangHS, ChuDT, et al. (2001) Specific and nonspecific NK cell activation during virus infection. Nat Immunol 2: 951–956.

22. SunJC, MaderaS, BezmanNA, BeilkeJN, KaplanMH, et al. (2012) Proinflammatory cytokine signaling required for the generation of natural killer cell memory. J Exp Med 209: 947–954.

23. NabekuraT, KanayaM, ShibuyaA, FuG, GascoigneNR, et al. (2014) Costimulatory molecule DNAM-1 is essential for optimal differentiation of memory natural killer cells during mouse cytomegalovirus infection. Immunity 40: 225–234.

24. BeaulieuAM, ZawislakCL, NakayamaT, SunJC (2014) The transcription factor Zbtb32 controls the proliferative burst of virus-specific natural killer cells responding to infection. Nat Immunol 15: 546–553.

25. Min-OoG, BezmanNA, MaderaS, SunJC, LanierLL (2014) Proapoptotic Bim regulates antigen-specific NK cell contraction and the generation of the memory NK cell pool after cytomegalovirus infection. J Exp Med 211: 1289–1296.

26. FirthMA, MaderaS, BeaulieuAM, GasteigerG, CastilloEF, et al. (2013) Nfil3-independent lineage maintenance and antiviral response of natural killer cells. J Exp Med 210: 2981–2990.

27. ZawislakCL, BeaulieuAM, LoebGB, KaroJ, CannerD, et al. (2013) Stage-specific regulation of natural killer cell homeostasis and response against viral infection by microRNA-155. Proc Natl Acad Sci U S A 110: 6967–6972.

28. GumaM, AnguloA, VilchesC, Gomez-LozanoN, MalatsN, et al. (2004) Imprint of human cytomegalovirus infection on the NK cell receptor repertoire. Blood 104: 3664–3671.

29. GumaM, BudtM, SaezA, BrckaloT, HengelH, et al. (2006) Expansion of CD94/NKG2C+ NK cells in response to human cytomegalovirus-infected fibroblasts. Blood 107: 3624–3631.

30. FoleyB, CooleyS, VernerisMR, PittM, CurtsingerJ, et al. (2012) Cytomegalovirus reactivation after allogeneic transplantation promotes a lasting increase in educated NKG2C+ natural killer cells with potent function. Blood 119: 2665–2674.

31. Lopez-VergesS, MilushJM, SchwartzBS, PandoMJ, JarjouraJ, et al. (2011) Expansion of a unique CD57(+)NKG2Chi natural killer cell subset during acute human cytomegalovirus infection. Proc Natl Acad Sci U S A 108: 14725–14732.

32. FoleyB, CooleyS, VernerisMR, CurtsingerJ, LuoX, et al. (2012) Human cytomegalovirus (CMV)-induced memory-like NKG2C(+) NK cells are transplantable and expand in vivo in response to recipient CMV antigen. J Immunol 189: 5082–5088.

33. KuijpersTW, BaarsPA, DantinC, van den BurgM, van LierRA, et al. (2008) Human NK cells can control CMV infection in the absence of T cells. Blood 112: 914–915.

34. BeziatV, DalgardO, AsselahT, HalfonP, BedossaP, et al. (2012) CMV drives clonal expansion of NKG2C+ NK cells expressing self-specific KIRs in chronic hepatitis patients. Eur J Immunol 42: 447–457.

35. BraudVM, AllanDS, O'CallaghanCA, SoderstromK, D'AndreaA, et al. (1998) HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C. Nature 391: 795–799.

36. BorregoF, UlbrechtM, WeissEH, ColiganJE, BrooksAG (1998) Recognition of human histocompatibility leukocyte antigen (HLA)-E complexed with HLA class I signal sequence-derived peptides by CD94/NKG2 confers protection from natural killer cell-mediated lysis. J Exp Med 187: 813–818.

37. LeeN, LlanoM, CarreteroM, IshitaniA, NavarroF, et al. (1998) HLA-E is a major ligand for the natural killer inhibitory receptor CD94/NKG2A. Proc Natl Acad Sci U S A 95: 5199–5204.

38. BraudV, JonesEY, McMichaelA (1997) The human major histocompatibility complex class Ib molecule HLA-E binds signal sequence-derived peptides with primary anchor residues at positions 2 and 9. Eur J Immunol 27: 1164–1169.

39. LeeN, GoodlettDR, IshitaniA, MarquardtH, GeraghtyDE (1998) HLA-E surface expression depends on binding of TAP-dependent peptides derived from certain HLA class I signal sequences. J Immunol 160: 4951–4960.

40. TomasecP, BraudVM, RickardsC, PowellMB, McSharryBP, et al. (2000) Surface expression of HLA-E, an inhibitor of natural killer cells, enhanced by human cytomegalovirus gpUL40. Science 287: 1031.

41. HeatleySL, PietraG, LinJ, WidjajaJM, HarpurCM, et al. (2013) Polymorphism in human cytomegalovirus UL40 impacts on recognition of human leukocyte antigen-E (HLA-E) by natural killer cells. J Biol Chem 288: 8679–8690.

42. PloeghHL (1998) Viral strategies of immune evasion. Science 280: 248–253.

43. Vales-GomezM, ReyburnHT, ErskineRA, Lopez-BotetM, StromingerJL (1999) Kinetics and peptide dependency of the binding of the inhibitory NK receptor CD94/NKG2-A and the activating receptor CD94/NKG2-C to HLA-E. EMBO J 18: 4250–4260.

44. BeziatV, LiuLL, MalmbergJA, IvarssonMA, SohlbergE, et al. (2013) NK cell responses to cytomegalovirus infection lead to stable imprints in the human KIR repertoire and involve activating KIRs. Blood 121: 2678–2688.

45. KalliesA, NuttSL (2007) Terminal differentiation of lymphocytes depends on Blimp-1. Curr Opin Immunol 19: 156–162.

46. OmoriM, YamashitaM, InamiM, Ukai-TadenumaM, KimuraM, et al. (2003) CD8 T cell-specific downregulation of histone hyperacetylation and gene activation of the IL-4 gene locus by ROG, repressor of GATA. Immunity 19: 281–294.

47. MiawSC, ChoiA, YuE, KishikawaH, HoIC (2000) ROG, repressor of GATA, regulates the expression of cytokine genes. Immunity 12: 323–333.

48. KlugM, RehliM (2006) Functional analysis of promoter CpG methylation using a CpG-free luciferase reporter vector. Epigenetics 1: 127–130.

49. BrycesonYT, MarchME, LjunggrenHG, LongEO (2006) Synergy among receptors on resting NK cells for the activation of natural cytotoxicity and cytokine secretion. Blood 107: 159–166.

50. SivoriS, ParoliniS, FalcoM, MarcenaroE, BiassoniR, et al. (2000) 2B4 functions as a co-receptor in human NK cell activation. Eur J Immunol 30: 787–793.

51. WhiteDW, Suzanne BeardR, BartonES (2012) Immune modulation during latent herpesvirus infection. Immunol Rev 245: 189–208.

52. SylwesterAW, MitchellBL, EdgarJB, TaorminaC, PelteC, et al. (2005) Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects. J Exp Med 202: 673–685.

53. MossP, KhanN (2004) CD8(+) T-cell immunity to cytomegalovirus. Hum Immunol 65: 456–464.

54. BironCA, NguyenKB, PienGC, CousensLP, Salazar-MatherTP (1999) Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu Rev Immunol 17: 189–220.

55. BjorkstromNK, LindgrenT, StoltzM, FauriatC, BraunM, et al. (2011) Rapid expansion and long-term persistence of elevated NK cell numbers in humans infected with hantavirus. J Exp Med 208: 13–21.

56. PetitdemangeC, BecquartP, WauquierN, BeziatV, DebreP, et al. (2011) Unconventional repertoire profile is imprinted during acute chikungunya infection for natural killer cells polarization toward cytotoxicity. PLoS Pathog 7: e1002268.

57. SandalovaE, LaccabueD, BoniC, TanAT, FinkK, et al. (2010) Contribution of herpesvirus specific CD8 T cells to anti-viral T cell response in humans. PLoS Pathog 6: e1001051.

58. WelshRM, CheJW, BrehmMA, SelinLK (2010) Heterologous immunity between viruses. Immunol Rev 235: 244–266.

59. TuuminenT, KekalainenE, MakelaS, Ala-HouhalaI, EnnisFA, et al. (2007) Human CD8+ T cell memory generation in Puumala hantavirus infection occurs after the acute phase and is associated with boosting of EBV-specific CD8+ memory T cells. J Immunol 179: 1988–1995.

60. BjorkstromNK, RieseP, HeutsF, AnderssonS, FauriatC, et al. (2010) Expression patterns of NKG2A, KIR, and CD57 define a process of CD56dim NK-cell differentiation uncoupled from NK-cell education. Blood 116: 3853–3864.

61. FosterSL, HargreavesDC, MedzhitovR (2007) Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature 447: 972–978.

62. PathakSK, BasuS, BhattacharyyaA, PathakS, BanerjeeA, et al. (2006) TLR4-dependent NF-kappaB activation and mitogen- and stress-activated protein kinase 1-triggered phosphorylation events are central to Helicobacter pylori peptidyl prolyl cis-, trans-isomerase (HP0175)-mediated induction of IL-6 release from macrophages. J Immunol 177: 7950–7958.

63. LoetscherP, UguccioniM, BordoliL, BaggioliniM, MoserB, et al. (1998) CCR5 is characteristic of Th1 lymphocytes. Nature 391: 344–345.

64. SattlerA, WagnerU, RossolM, SieperJ, WuP, et al. (2009) Cytokine-induced human IFN-gamma-secreting effector-memory Th cells in chronic autoimmune inflammation. Blood 113: 1948–1956.

65. BoyleP, ClementK, GuH, SmithZD, ZillerM, et al. (2012) Gel-free multiplexed reduced representation bisulfite sequencing for large-scale DNA methylation profiling. Genome Biol 13: R92.

66. MartinM (2011) Cutadapt removes adapter sequences from high-throughput sequencing reads. EMBnetjournal 17: 10–12.

67. WuTD, NacuS (2010) Fast and SNP-tolerant detection of complex variants and splicing in short reads. Bioinformatics 26: 873–881.

68. LiuY, SiegmundKD, LairdPW, BermanBP (2012) Bis-SNP: Combined DNA methylation and SNP calling for Bisulfite-seq data. Genome Biol 13: R61.

69. AssenovY, MüllerF, LutsikP, WalterJ, LengauerT, et al. (2014) Comprehensive Analysis of DNA Methylation Data with RnBeads. Nature Methods [in press].

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Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

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