Murine Gammaherpesvirus M2 Protein Induction of IRF4 via the NFAT Pathway Leads to IL-10 Expression in B Cells

English version České info

Reactivation of the gammaherpesviruses Epstein-Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus (KSHV) and murine gammaherpesvirus 68 (MHV68) from latently infected B cells has been linked to plasma cell differentiation. We have previously shown that the MHV68 M2 protein is important for virus reactivation from B cells and, when expressed alone in primary murine B cells, can drive B cell differentiation towards a pre-plasma cell phenotype. In addition, expression of M2 in primary murine B cells leads to secretion of high levels of IL-10 along with enhanced proliferation and survival. Furthermore, the absence of M2 in vivo leads to a defect in the appearance of MHV68 infected plasma cells in the spleen at the peak of MHV68 latency. Here, employing an inducible B cell expression system, we have determined that M2 activates the NFAT pathway in a Src kinase-dependent manner – leading to induction of the plasma cell-associated transcription factor, Interferon Regulatory Factor-4 (IRF4). Furthermore, we show that expression of IRF4 alone in a B cell line up-regulates IL-10 expression in culture supernatants, revealing a novel role for IRF4 in B cell induced IL-10. Consistent with the latter observation, we show that IRF4 can regulate the IL-10 promoter in B cells. In primary murine B cells, addition of cyclosporine (CsA) resulted in a significant decrease in M2-induced IL-10 levels as well as IRF4 expression, emphasizing the importance of the NFAT pathway in M2- mediated induction of IL-10. Together, these studies argue in favor of a model wherein M2 activation of the NFAT pathway initiates events leading to increased levels of IRF4 – a key player in plasma cell differentiation – which in turn triggers IL-10 expression. In the context of previous findings, the data presented here provides insights into how M2 facilitates plasma cell differentiation and subsequent virus reactivation.

Vyšlo v časopise: Murine Gammaherpesvirus M2 Protein Induction of IRF4 via the NFAT Pathway Leads to IL-10 Expression in B Cells. PLoS Pathog 10(1): e32767. doi:10.1371/journal.ppat.1003858
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1003858

Souhrn

Zdroje

1. DamaniaB (2004) Oncogenic gamma-herpesviruses: comparison of viral proteins involved in tumorigenesis. Nat Rev Microbiol 2: 656–668.

2. BlaskovicD, StancekovaM, SvobodovaJ, MistrikovaJ (1980) Isolation of five strains of herpesviruses from two species of free living small rodents. Acta Virol 24: 468.

3. BlasdellK, McCrackenC, MorrisA, NashAA, BegonM, et al. (2003) The wood mouse is a natural host for Murid herpesvirus 4. J Gen Virol 84: 111–113.

4. UsherwoodEJ, StewartJP, RobertsonK, AllenDJ, NashAA (1996) Absence of splenic latency in murine gammaherpesvirus 68-infected B cell-deficient mice. J Gen Virol 77 (Pt 11) 2819–2825.

5. WeckKE, KimSS, VirginHI, SpeckSH (1999) B cells regulate murine gammaherpesvirus 68 latency. J Virol 73: 4651–4661.

6. Sunil-ChandraNP, EfstathiouS, ArnoJ, NashAA (1992) Virological and pathological features of mice infected with murine gamma-herpesvirus 68. J Gen Virol 73 (Pt 9) 2347–2356.

7. BartonE, MandalP, SpeckSH (2011) Pathogenesis and host control of gammaherpesviruses: lessons from the mouse. Annu Rev Immunol 29: 351–397.

8. MoserJM, UptonJW, AllenRD3rd, WilsonCB, SpeckSH (2005) Role of B-cell proliferation in the establishment of gammaherpesvirus latency. J Virol 79: 9480–9491.

9. WarmingS, CostantinoN, CourtDL, JenkinsNA, CopelandNG (2005) Simple and highly efficient BAC recombineering using galK selection. Nucleic Acids Res 33: e36.

10. MiyazakiI, CheungRK, DoschHM (1993) Viral interleukin 10 is critical for the induction of B cell growth transformation by Epstein-Barr virus. J Exp Med 178: 439–447.

11. LeeBS, LeeSH, FengP, ChangH, ChoNH, et al. (2005) Characterization of the Kaposi's sarcoma-associated herpesvirus K1 signalosome. J Virol 79: 12173–12184.

12. LagunoffM, MajetiR, WeissA, GanemD (1999) Deregulated signal transduction by the K1 gene product of Kaposi's sarcoma-associated herpesvirus. Proc Natl Acad Sci U S A 96: 5704–5709.

13. HerskowitzJH, JacobyMA, SpeckSH (2005) The murine gammaherpesvirus 68 M2 gene is required for efficient reactivation from latently infected B cells. J Virol 79: 2261–2273.

14. JacobyMA, VirginHWt, SpeckSH (2002) Disruption of the M2 gene of murine gammaherpesvirus 68 alters splenic latency following intranasal, but not intraperitoneal, inoculation. J Virol 76: 1790–1801.

15. LiangX, CollinsCM, MendelJB, IwakoshiNN, SpeckSH (2009) Gammaherpesvirus-driven plasma cell differentiation regulates virus reactivation from latently infected B lymphocytes. PLoS Pathog 5: e1000677.

16. SiegelAM, HerskowitzJH, SpeckSH (2008) The MHV68 M2 protein drives IL-10 dependent B cell proliferation and differentiation. PLoS Pathog 4: e1000039.

17. HerskowitzJH, SiegelAM, JacobyMA, SpeckSH (2008) Systematic mutagenesis of the murine gammaherpesvirus 68 M2 protein identifies domains important for chronic infection. J Virol 82: 3295–3310.

18. Pires de MirandaM, AlenquerM, MarquesS, RodriguesL, LopesF, et al. (2008) The Gammaherpesvirus m2 protein manipulates the Fyn/Vav pathway through a multidocking mechanism of assembly. PLoS One 3: e1654.

19. Pires de MirandaM, LopesFB, McVeyCE, BusteloXR, SimasJP (2013) Role of Src homology domain binding in signaling complexes assembled by the murid gamma-herpesvirus M2 protein. J Biol Chem 288: 3858–3870.

20. WeberM, TreanorB, DepoilD, ShinoharaH, HarwoodNE, et al. (2008) Phospholipase C-gamma2 and Vav cooperate within signaling microclusters to propagate B cell spreading in response to membrane-bound antigen. J Exp Med 205: 853–868.

21. FuC, TurckCW, KurosakiT, ChanAC (1998) BLNK: a central linker protein in B cell activation. Immunity 9: 93–103.

22. HarwoodNE, BatistaFD (2010) Early events in B cell activation. Annu Rev Immunol 28: 185–210.

23. KurosakiT, ShinoharaH, BabaY (2010) B cell signaling and fate decision. Annu Rev Immunol 28: 21–55.

24. RaoA, LuoC, HoganPG (1997) Transcription factors of the NFAT family: regulation and function. Annu Rev Immunol 15: 707–747.

25. BerlandR, WortisHH (2003) Normal B-1a cell development requires B cell-intrinsic NFATc1 activity. Proc Natl Acad Sci U S A 100: 13459–13464.

26. WinslowMM, GalloEM, NeilsonJR, CrabtreeGR (2006) The calcineurin phosphatase complex modulates immunogenic B cell responses. Immunity 24: 141–152.

27. De SilvaNS, SimonettiG, HeiseN, KleinU (2012) The diverse roles of IRF4 in late germinal center B-cell differentiation. Immunol Rev 247: 73–92.

28. SciammasR, ShafferAL, SchatzJH, ZhaoH, StaudtLM, et al. (2006) Graded expression of interferon regulatory factor-4 coordinates isotype switching with plasma cell differentiation. Immunity 25: 225–236.

29. KleinU, CasolaS, CattorettiG, ShenQ, LiaM, et al. (2006) Transcription factor IRF4 controls plasma cell differentiation and class-switch recombination. Nat Immunol 7: 773–782.

30. AhyiAN, ChangHC, DentAL, NuttSL, KaplanMH (2009) IFN regulatory factor 4 regulates the expression of a subset of Th2 cytokines. J Immunol 183: 1598–1606.

31. HonmaK, KimuraD, TominagaN, MiyakodaM, MatsuyamaT, et al. (2008) Interferon regulatory factor 4 differentially regulates the production of Th2 cytokines in naive vs. effector/memory CD4+ T cells. Proc Natl Acad Sci U S A 105: 15890–15895.

32. LeeCG, HwangW, MaengKE, KwonHK, SoJS, et al. (2011) IRF4 regulates IL-10 gene expression in CD4(+) T cells through differential nuclear translocation. Cell Immunol 268: 97–104.

33. LeeCG, KangKH, SoJS, KwonHK, SonJS, et al. (2009) A distal cis-regulatory element, CNS-9, controls NFAT1 and IRF4-mediated IL-10 gene activation in T helper cells. Mol Immunol 46: 613–621.

34. LohoffM, MittruckerHW, PrechtlS, BischofS, SommerF, et al. (2002) Dysregulated T helper cell differentiation in the absence of interferon regulatory factor 4. Proc Natl Acad Sci U S A 99: 11808–11812.

35. ZhengY, ChaudhryA, KasA, deRoosP, KimJM, et al. (2009) Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. Nature 458: 351–356.

36. ChoeJ, ChoiYS (1998) IL-10 interrupts memory B cell expansion in the germinal center by inducing differentiation into plasma cells. Eur J Immunol 28: 508–515.

37. BurdinN, Van KootenC, GalibertL, AbramsJS, WijdenesJ, et al. (1995) Endogenous IL-6 and IL-10 contribute to the differentiation of CD40-activated human B lymphocytes. J Immunol 154: 2533–2544.

38. ItohK, HirohataS (1995) The role of IL-10 in human B cell activation, proliferation, and differentiation. J Immunol 154: 4341–4350.

39. KobayashiN, NagumoH, AgematsuK (2002) IL-10 enhances B-cell IgE synthesis by promoting differentiation into plasma cells, a process that is inhibited by CD27/CD70 interaction. Clin Exp Immunol 129: 446–452.

40. MooreKW, VieiraP, FiorentinoDF, TrounstineML, KhanTA, et al. (1990) Homology of cytokine synthesis inhibitory factor (IL-10) to the Epstein-Barr virus gene BCRFI. Science 248: 1230–1234.

41. QinZ, KearneyP, PlaisanceK, ParsonsCH (2010) Pivotal advance: Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded microRNA specifically induce IL-6 and IL-10 secretion by macrophages and monocytes. J Leukoc Biol 87: 25–34.

42. EjrnaesM, FilippiCM, MartinicMM, LingEM, TogherLM, et al. (2006) Resolution of a chronic viral infection after interleukin-10 receptor blockade. J Exp Med 203: 2461–2472.

43. BrooksDG, TrifiloMJ, EdelmannKH, TeytonL, McGavernDB, et al. (2006) Interleukin-10 determines viral clearance or persistence in vivo. Nat Med 12: 1301–1309.

44. BrockmanMA, KwonDS, TigheDP, PavlikDF, RosatoPC, et al. (2009) IL-10 is up-regulated in multiple cell types during viremic HIV infection and reversibly inhibits virus-specific T cells. Blood 114: 346–356.

45. 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 33: 3448–3457.

46. MadanR, DemircikF, SurianarayananS, AllenJL, DivanovicS, et al. (2009) Nonredundant roles for B cell-derived IL-10 in immune counter-regulation. J Immunol 183: 2312–2320.

47. AlcamiA (2003) Viral mimicry of cytokines, chemokines and their receptors. Nat Rev Immunol 3: 36–50.

48. MadureiraPA, MatosP, SoeiroI, DixonLK, SimasJP, et al. (2005) Murine gamma-herpesvirus 68 latency protein M2 binds to Vav signaling proteins and inhibits B-cell receptor-induced cell cycle arrest and apoptosis in WEHI-231 B cells. J Biol Chem 280: 37310–37318.

49. RodriguesL, Pires de MirandaM, CalocaMJ, BusteloXR, SimasJP (2006) Activation of Vav by the gammaherpesvirus M2 protein contributes to the establishment of viral latency in B lymphocytes. J Virol 80: 6123–6135.

50. LiangX, ShinYC, MeansRE, JungJU (2004) Inhibition of interferon-mediated antiviral activity by murine gammaherpesvirus 68 latency-associated M2 protein. J Virol 78: 12416–12427.

51. MacianF, Garcia-RodriguezC, RaoA (2000) Gene expression elicited by NFAT in the presence or absence of cooperative recruitment of Fos and Jun. EMBO J 19: 4783–4795.

52. RengarajanJ, MowenKA, McBrideKD, SmithED, SinghH, et al. (2002) Interferon regulatory factor 4 (IRF4) interacts with NFATc2 to modulate interleukin 4 gene expression. J Exp Med 195: 1003–1012.

53. ClipstoneNA, CrabtreeGR (1992) Identification of calcineurin as a key signalling enzyme in T-lymphocyte activation. Nature 357: 695–697.

54. DolmetschRE, LewisRS, GoodnowCC, HealyJI (1997) Differential activation of transcription factors induced by Ca2+ response amplitude and duration. Nature 386: 855–858.

55. GrumontRJ, GerondakisS (2000) Rel induces interferon regulatory factor 4 (IRF-4) expression in lymphocytes: modulation of interferon-regulated gene expression by rel/nuclear factor kappaB. J Exp Med 191: 1281–1292.

56. MittruckerHW, MatsuyamaT, GrossmanA, KundigTM, PotterJ, et al. (1997) Requirement for the transcription factor LSIRF/IRF4 for mature B and T lymphocyte function. Science 275: 540–543.

57. GuptaS, JiangM, AnthonyA, PernisAB (1999) Lineage-specific modulation of interleukin 4 signaling by interferon regulatory factor 4. J Exp Med 190: 1837–1848.

58. BrustleA, HeinkS, HuberM, RosenplanterC, StadelmannC, et al. (2007) The development of inflammatory T(H)-17 cells requires interferon-regulatory factor 4. Nat Immunol 8: 958–966.

59. BolligN, BrustleA, KellnerK, AckermannW, AbassE, et al. (2012) Transcription factor IRF4 determines germinal center formation through follicular T-helper cell differentiation. Proc Natl Acad Sci U S A 109: 8664–8669.

60. WangZY, SatoH, KusamS, SehraS, ToneyLM, et al. (2005) Regulation of IL-10 gene expression in Th2 cells by Jun proteins. J Immunol 174: 2098–2105.

61. BrightbillHD, PlevySE, ModlinRL, SmaleST (2000) A prominent role for Sp1 during lipopolysaccharide-mediated induction of the IL-10 promoter in macrophages. J Immunol 164: 1940–1951.

62. JonesEA, FlavellRA (2005) Distal enhancer elements transcribe intergenic RNA in the IL-10 family gene cluster. J Immunol 175: 7437–7446.

63. IwakoshiNN, LeeAH, VallabhajosyulaP, OtipobyKL, RajewskyK, et al. (2003) Plasma cell differentiation and the unfolded protein response intersect at the transcription factor XBP-1. Nat Immunol 4: 321–329.

64. BhattacharyyaS, DebJ, PatraAK, Thuy PhamDA, ChenW, et al. (2011) NFATc1 affects mouse splenic B cell function by controlling the calcineurin–NFAT signaling network. J Exp Med 208: 823–839.

65. GuptaS, AnthonyA, PernisAB (2001) Stage-specific modulation of IFN-regulatory factor 4 function by Kruppel-type zinc finger proteins. J Immunol 166: 6104–6111.

66. OchiaiK, Maienschein-ClineM, SimonettiG, ChenJ, RosenthalR, et al. (2013) Transcriptional regulation of germinal center B and plasma cell fates by dynamical control of IRF4. Immunity 38: 918–929.

67. CollinsCM, SpeckSH (2012) Tracking murine gammaherpesvirus 68 infection of germinal center B cells in vivo. PLoS One 7: e33230.

68. PadenCR, ForrestJC, TibbettsSA, SpeckSH (2012) Unbiased mutagenesis of MHV68 LANA reveals a DNA-binding domain required for LANA function in vitro and in vivo. PLoS Pathog 8: e1002906.

69. WilsonSJ, TsaoEH, WebbBL, YeH, Dalton-GriffinL, et al. (2007) X box binding protein XBP-1s transactivates the Kaposi's sarcoma-associated herpesvirus (KSHV) ORF50 promoter, linking plasma cell differentiation to KSHV reactivation from latency. J Virol 81: 13578–13586.

70. YuF, FengJ, HaradaJN, ChandaSK, KenneySC, et al. (2007) B cell terminal differentiation factor XBP-1 induces reactivation of Kaposi's sarcoma-associated herpesvirus. FEBS Lett 581: 3485–3488.

71. LaichalkLL, Thorley-LawsonDA (2005) Terminal differentiation into plasma cells initiates the replicative cycle of Epstein-Barr virus in vivo. J Virol 79: 1296–1307.

72. MasedaD, SmithSH, DiLilloDJ, BryantJM, CandandoKM, et al. (2012) Regulatory B10 cells differentiate into antibody-secreting cells after transient IL-10 production in vivo. J Immunol 188: 1036–1048.

73. MatsumotoM, FujiiY, BabaA, HikidaM, KurosakiT, et al. (2011) The calcium sensors STIM1 and STIM2 control B cell regulatory function through interleukin-10 production. Immunity 34: 703–714.

74. KalampokisI, YoshizakiA, TedderTF (2013) IL-10-producing regulatory B cells (B10 cells) in autoimmune disease. Arthritis Res Ther 15 (Suppl 1) S1.

75. MatsushitaT, TedderTF (2011) Identifying regulatory B cells (B10 cells) that produce IL-10 in mice. Methods Mol Biol 677: 99–111.

76. PoeJC, SmithSH, HaasKM, YanabaK, TsubataT, et al. (2011) Amplified B lymphocyte CD40 signaling drives regulatory B10 cell expansion in mice. PLoS One 6: e22464.

77. YanabaK, BouazizJD, MatsushitaT, TsubataT, TedderTF (2009) The development and function of regulatory B cells expressing IL-10 (B10 cells) requires antigen receptor diversity and TLR signals. J Immunol 182: 7459–7472.

78. YoshizakiA, MiyagakiT, DiLilloDJ, MatsushitaT, HorikawaM, et al. (2012) Regulatory B cells control T-cell autoimmunity through IL-21-dependent cognate interactions. Nature 491: 264–268.

79. YanabaK, BouazizJD, HaasKM, PoeJC, FujimotoM, et al. (2008) A regulatory B cell subset with a unique CD1dhiCD5+ phenotype controls T cell-dependent inflammatory responses. Immunity 28: 639–650.

80. LiangX, PickeringMT, ChoNH, ChangH, VolkertMR, et al. (2006) Deregulation of DNA damage signal transduction by herpesvirus latency-associated M2. J Virol 80: 5862–5874.

81. PernisAB (2002) The role of IRF-4 in B and T cell activation and differentiation. J Interferon Cytokine Res 22: 111–120.

82. CretneyE, XinA, ShiW, MinnichM, MassonF, et al. (2011) The transcription factors Blimp-1 and IRF4 jointly control the differentiation and function of effector regulatory T cells. Nat Immunol 12: 304–311.

83. XuD, ZhaoL, Del ValleL, MiklossyJ, ZhangL (2008) Interferon regulatory factor 4 is involved in Epstein-Barr virus-mediated transformation of human B lymphocytes. J Virol 82: 6251–6258.

84. TakaharaM, KisLL, NagyN, LiuA, HarabuchiY, et al. (2006) Concomitant increase of LMP1 and CD25 (IL-2-receptor alpha) expression induced by IL-10 in the EBV-positive NK lines SNK6 and KAI3. Int J Cancer 119: 2775–2783.

85. LambertSL, MartinezOM (2007) Latent membrane protein 1 of EBV activates phosphatidylinositol 3-kinase to induce production of IL-10. J Immunol 179: 8225–8234.

86. KisLL, TakaharaM, NagyN, KleinG, KleinE (2006) IL-10 can induce the expression of EBV-encoded latent membrane protein-1 (LMP-1) in the absence of EBNA-2 in B lymphocytes and in Burkitt lymphoma- and NK lymphoma-derived cell lines. Blood 107: 2928–2935.

87. NakagomiH, DolcettiR, BejaranoMT, PisaP, KiesslingR, et al. (1994) The Epstein-Barr virus latent membrane protein-1 (LMP1) induces interleukin-10 production in Burkitt lymphoma lines. Int J Cancer 57: 240–244.

88. VockerodtM, HaierB, ButtgereitP, TeschH, KubeD (2001) The Epstein-Barr virus latent membrane protein 1 induces interleukin-10 in Burkitt's lymphoma cells but not in Hodgkin's cells involving the p38/SAPK2 pathway. Virology 280: 183–198.

89. GoldfeldAE, LiuP, LiuS, FlemingtonEK, StromingerJL, et al. (1995) Cyclosporin A and FK506 block induction of the Epstein-Barr virus lytic cycle by anti-immunoglobulin. Virology 209: 225–229.

90. LiuS, LiuP, BorrasA, ChatilaT, SpeckSH (1997) Cyclosporin A-sensitive induction of the Epstein-Barr virus lytic switch is mediated via a novel pathway involving a MEF2 family member. EMBO J 16: 143–153.

91. ZoeteweijJP, MosesAV, RinderknechtAS, DavisDA, OverwijkWW, et al. (2001) Targeted inhibition of calcineurin signaling blocks calcium-dependent reactivation of Kaposi sarcoma-associated herpesvirus. Blood 97: 2374–2380.

92. LeeH, GuoJ, LiM, ChoiJK, DeMariaM, et al. (1998) Identification of an immunoreceptor tyrosine-based activation motif of K1 transforming protein of Kaposi's sarcoma-associated herpesvirus. Mol Cell Biol 18: 5219–5228.

93. LukacDM, RenneR, KirshnerJR, GanemD (1998) Reactivation of Kaposi's sarcoma-associated herpesvirus infection from latency by expression of the ORF 50 transactivator, a homolog of the EBV R protein. Virology 252: 304–312.

94. WeckKE, KimSS, VirginHI, SpeckSH (1999) Macrophages are the major reservoir of latent murine gammaherpesvirus 68 in peritoneal cells. J Virol 73: 3273–3283.

95. WeckKE, BarkonML, YooLI, SpeckSH, VirginHI (1996) Mature B cells are required for acute splenic infection, but not for establishment of latency, by murine gammaherpesvirus 68. J Virol 70: 6775–6780.