Foxp3 Regulatory T Cells Delay Expulsion of Intestinal Nematodes by Suppression of IL-9-Driven Mast Cell Activation in BALB/c but Not in C57BL/6 Mice


Accumulating evidence suggests that IL-9-mediated immunity plays a fundamental role in control of intestinal nematode infection. Here we report a different impact of Foxp3+ regulatory T cells (Treg) in nematode-induced evasion of IL-9-mediated immunity in BALB/c and C57BL/6 mice. Infection with Strongyloides ratti induced Treg expansion with similar kinetics and phenotype in both strains. Strikingly, Treg depletion reduced parasite burden selectively in BALB/c but not in C57BL/6 mice. Treg function was apparent in both strains as Treg depletion increased nematode-specific humoral and cellular Th2 response in BALB/c and C57BL/6 mice to the same extent. Improved resistance in Treg-depleted BALB/c mice was accompanied by increased production of IL-9 and accelerated degranulation of mast cells. In contrast, IL-9 production was not significantly elevated and kinetics of mast cell degranulation were unaffected by Treg depletion in C57BL/6 mice. By in vivo neutralization, we demonstrate that increased IL-9 production during the first days of infection caused accelerated mast cell degranulation and rapid expulsion of S. ratti adults from the small intestine of Treg-depleted BALB/c mice. In genetically mast cell-deficient (Cpa3-Cre) BALB/c mice, Treg depletion still resulted in increased IL-9 production but resistance to S. ratti infection was lost, suggesting that IL-9-driven mast cell activation mediated accelerated expulsion of S. ratti in Treg-depleted BALB/c mice. This IL-9-driven mast cell degranulation is a central mechanism of S. ratti expulsion in both, BALB/c and C57BL/6 mice, because IL-9 injection reduced and IL-9 neutralization increased parasite burden in the presence of Treg in both strains. Therefore our results suggest that Foxp3+ Treg suppress sufficient IL-9 production for subsequent mast cell degranulation during S. ratti infection in a non-redundant manner in BALB/c mice, whereas additional regulatory pathways are functional in Treg-depleted C57BL/6 mice.


Vyšlo v časopise: Foxp3 Regulatory T Cells Delay Expulsion of Intestinal Nematodes by Suppression of IL-9-Driven Mast Cell Activation in BALB/c but Not in C57BL/6 Mice. PLoS Pathog 10(2): e32767. doi:10.1371/journal.ppat.1003913
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1003913

Souhrn

Accumulating evidence suggests that IL-9-mediated immunity plays a fundamental role in control of intestinal nematode infection. Here we report a different impact of Foxp3+ regulatory T cells (Treg) in nematode-induced evasion of IL-9-mediated immunity in BALB/c and C57BL/6 mice. Infection with Strongyloides ratti induced Treg expansion with similar kinetics and phenotype in both strains. Strikingly, Treg depletion reduced parasite burden selectively in BALB/c but not in C57BL/6 mice. Treg function was apparent in both strains as Treg depletion increased nematode-specific humoral and cellular Th2 response in BALB/c and C57BL/6 mice to the same extent. Improved resistance in Treg-depleted BALB/c mice was accompanied by increased production of IL-9 and accelerated degranulation of mast cells. In contrast, IL-9 production was not significantly elevated and kinetics of mast cell degranulation were unaffected by Treg depletion in C57BL/6 mice. By in vivo neutralization, we demonstrate that increased IL-9 production during the first days of infection caused accelerated mast cell degranulation and rapid expulsion of S. ratti adults from the small intestine of Treg-depleted BALB/c mice. In genetically mast cell-deficient (Cpa3-Cre) BALB/c mice, Treg depletion still resulted in increased IL-9 production but resistance to S. ratti infection was lost, suggesting that IL-9-driven mast cell activation mediated accelerated expulsion of S. ratti in Treg-depleted BALB/c mice. This IL-9-driven mast cell degranulation is a central mechanism of S. ratti expulsion in both, BALB/c and C57BL/6 mice, because IL-9 injection reduced and IL-9 neutralization increased parasite burden in the presence of Treg in both strains. Therefore our results suggest that Foxp3+ Treg suppress sufficient IL-9 production for subsequent mast cell degranulation during S. ratti infection in a non-redundant manner in BALB/c mice, whereas additional regulatory pathways are functional in Treg-depleted C57BL/6 mice.


Zdroje

1. McSorleyHJ, MaizelsRM (2012) Helminth infections and host immune regulation. Clin Microbiol Rev 25: 585–608.

2. MaizelsRM, BalicA, Gomez-EscobarN, NairM, TaylorMD, et al. (2004) Helminth parasites–masters of regulation. Immunol Rev 201: 89–116.

3. SakaguchiS, SakaguchiN, AsanoM, ItohM, TodaM (1995) Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. Journal of Immunology 155: 1151–1164.

4. WingK, SakaguchiS (2010) Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat Immunol 11: 7–13.

5. WammesLJ, HamidF, WiriaAE, WibowoH, SartonoE, et al. (2012) Regulatory T cells in human lymphatic filariasis: stronger functional activity in microfilaremics. PLoS Negl Trop Dis 6: e1655.

6. WammesLJ, HamidF, WiriaAE, de GierB, SartonoE, et al. (2010) Regulatory T cells in human geohelminth infection suppress immune responses to BCG and Plasmodium falciparum. Eur J Immunol 40: 437–442.

7. MetenouS, DembeleB, KonateS, DoloH, CoulibalySY, et al. (2010) At homeostasis filarial infections have expanded adaptive T regulatory but not classical Th2 cells. J Immunol 184: 5375–5382.

8. NauschN, MidziN, MduluzaT, MaizelsRM, MutapiF (2011) Regulatory and activated T cells in human Schistosoma haematobium infections. PLoS ONE 6: e16860.

9. MontesM, SanchezC, VerdonckK, LakeJE, GonzalezE, et al. (2009) Regulatory T cell expansion in HTLV-1 and strongyloidiasis co-infection is associated with reduced IL-5 responses to Strongyloides stercoralis antigen. PLoS Negl Trop Dis 3: e456.

10. FinneyCA, TaylorMD, WilsonMS, MaizelsRM (2007) Expansion and activation of CD4(+)CD25(+) regulatory T cells in Heligmosomoides polygyrus infection. Eur J Immunol 37: 1874–1886.

11. McSorleyHJ, HarcusYM, MurrayJ, TaylorMD, MaizelsRM (2008) Expansion of Foxp3+ regulatory T cells in mice infected with the filarial parasite Brugia malayi. J Immunol 181: 6456–6466.

12. RauschS, HuehnJ, KirchhoffD, RzepeckaJ, SchnoellerC, et al. (2008) Functional analysis of effector and regulatory T cells in a parasitic nematode infection. Infect Immun 76: 1908–1919.

13. TaylorMD, van der WerfN, HarrisA, GrahamAL, BainO, et al. (2009) Early recruitment of natural CD4+ Foxp3+ Treg cells by infective larvae determines the outcome of filarial infection. Eur J Immunol 39: 192–206.

14. BlankenhausB, KlemmU, EschbachML, SparwasserT, HuehnJ, et al. (2011) Strongyloides ratti infection induces expansion of Foxp3+ regulatory T cells that interfere with immune response and parasite clearance in BALB/c mice. Journal of Immunology 186: 4295–4305.

15. GraingerJR, SmithKA, HewitsonJP, McSorleyHJ, HarcusY, et al. (2010) Helminth secretions induce de novo T cell Foxp3 expression and regulatory function through the TGF-beta pathway. J Exp Med 207: 2331–2341.

16. TaylorJJ, MohrsM, PearceEJ (2006) Regulatory T cell responses develop in parallel to Th responses and control the magnitude and phenotype of the Th effector population. J Immunol 176: 5839–5847.

17. LaylandLE, RadR, WagnerH, da CostaCU (2007) Immunopathology in schistosomiasis is controlled by antigen-specific regulatory T cells primed in the presence of TLR2. Eur J Immunol 37: 2174–2184.

18. RauschS, HuehnJ, LoddenkemperC, HepworthMR, KlotzC, et al. (2009) Establishment of nematode infection despite increased Th2 responses and immunopathology after selective depletion of Foxp3+ cells. Eur J Immunol 39: 3066–3077.

19. D'EliaR, BehnkeJM, BradleyJE, ElseKJ (2009) Regulatory T cells: a role in the control of helminth-driven intestinal pathology and worm survival. J Immunol 182: 2340–2348.

20. WilsonMS, TaylorMD, BalicA, FinneyCA, LambJR, et al. (2005) Suppression of allergic airway inflammation by helminth-induced regulatory T cells. J Exp Med 202: 1199–1212.

21. DittrichAM, ErbacherA, SpechtS, DiesnerF, KrokowskiM, et al. (2008) Helminth infection with Litomosoides sigmodontis induces regulatory T cells and inhibits allergic sensitization, airway inflammation, and hyperreactivity in a murine asthma model. J Immunol 180: 1792–1799.

22. TetsutaniK, IshiwataK, IshidaH, TuL, ToriiM, et al. (2009) Concurrent infection with Heligmosomoides polygyrus suppresses anti-Plasmodium yoelii protection partially by induction of CD4(+)CD25(+)Foxp3(+) Treg in mice. Eur J Immunol 39: 2822–2830.

23. PacificoLG, MarinhoFA, FonsecaCT, BarsanteMM, PinhoV, et al. (2009) Schistosoma mansoni antigens modulate experimental allergic asthma in a murine model: a major role for CD4+ CD25+ Foxp3+ T cells independent of interleukin-10. Infect Immun 77: 98–107.

24. TaylorMD, van der WerfN, MaizelsRM (2012) T cells in helminth infection: the regulators and the regulated. Trends Immunol 33: 181–189.

25. FontenotJD, GavinMA, RudenskyAY (2003) Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 4: 330–336.

26. LahlK, LoddenkemperC, DrouinC, FreyerJ, ArnasonJ, et al. (2007) Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease. J Exp Med 204: 57–63.

27. KimJM, RasmussenJP, RudenskyAY (2007) Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol 8: 191–197.

28. LahlK, SparwasserT (2011) In vivo depletion of FoxP3+ Tregs using the DEREG mouse model. Methods in molecular biology 707: 157–172.

29. Viney ME, Lok JB (2007) Strongyloides spp. WormBook doi/10.1895/wormbook.1.141.1.available at http://www.wormbook.org.: 1–15.

30. UchikawaR, NojimaH, SatoA (1989) The effects of single and repeated inoculations of various larval doses on Strongyloides ratti burden and distribution in rats. J Parasitol 75: 577–584.

31. DawkinsHJ, GroveDI (1981) Kinetics of primary and secondary infections with Strongyloides ratti in mice. Int J Parasitol 11: 89–96.

32. WilkesCP, BleayC, PatersonS, VineyME (2007) The immune response during a Strongyloides ratti infection of rats. Parasite Immunol 29: 339–346.

33. EschbachML, KlemmU, KolbaumJ, BlankenhausB, BrattigN, et al. (2010) Strongyloides ratti infection induces transient nematode-specific Th2 response and reciprocal suppression of IFN-gamma production in mice. Parasite immunology 32: 370–383.

34. WatanabeK, NodaK, HamanoS, KogaM, KishiharaK, et al. (2000) The crucial role of granulocytes in the early host defense against Strongyloides ratti infection in mice. Parasitol Res 86: 188–193.

35. GaliotoAM, HessJA, NolanTJ, SchadGA, LeeJJ, et al. (2006) Role of eosinophils and neutrophils in innate and adaptive protective immunity to larval strongyloides stercoralis in mice. Infect Immun 74: 5730–5738.

36. KerepesiLA, HessJA, NolanTJ, SchadGA, AbrahamD (2006) Complement component C3 is required for protective innate and adaptive immunity to larval strongyloides stercoralis in mice. J Immunol 176: 4315–4322.

37. BrigandiRA, RotmanHL, YutanawiboonchaiW, LeonO, NolanTJ, et al. (1996) Strongyloides stercoralis: role of antibody and complement in immunity to the third stage of larvae in BALB/cByJ mice. Exp Parasitol 82: 279–289.

38. NawaY, KiyotaM, KorenagaM, KotaniM (1985) Defective protective capacity of W/Wv mice against Strongyloides ratti infection and its reconstitution with bone marrow cells. Parasite Immunol 7: 429–438.

39. FukaoT, YamadaT, TanabeM, TerauchiY, OtaT, et al. (2002) Selective loss of gastrointestinal mast cells and impaired immunity in PI3K-deficient mice. Nat Immunol 3: 295–304.

40. SasakiY, YoshimotoT, MaruyamaH, TegoshiT, OhtaN, et al. (2005) IL-18 with IL-2 protects against Strongyloides venezuelensis infection by activating mucosal mast cell-dependent type 2 innate immunity. J Exp Med 202: 607–616.

41. RodewaldHR, FeyerabendTB (2012) Widespread immunological functions of mast cells: fact or fiction? Immunity 37: 13–24.

42. Licona-LimonP, Henao-MejiaJ, TemannAU, GaglianiN, Licona-LimonI, et al. (2013) Th9 Cells Drive Host Immunity against Gastrointestinal Worm Infection. Immunity 39: 744–757.

43. TurnerJE, MorrisonPJ, WilhelmC, WilsonM, AhlforsH, et al. (2013) IL-9-mediated survival of type 2 innate lymphoid cells promotes damage control in helminth-induced lung inflammation. J Exp Med

44. HuehnJ, SiegmundK, LehmannJC, SiewertC, HauboldU, et al. (2004) Developmental stage, phenotype, and migration distinguish naive- and effector/memory-like CD4+ regulatory T cells. J Exp Med 199: 303–313.

45. SugimotoN, OidaT, HirotaK, NakamuraK, NomuraT, et al. (2006) Foxp3-dependent and -independent molecules specific for CD25+CD4+ natural regulatory T cells revealed by DNA microarray analysis. International immunology 18: 1197–1209.

46. WeissJM, BilateAM, GobertM, DingY, Curotto de LafailleMA, et al. (2012) Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3+ T reg cells. J Exp Med 209: 1723–1742, S1721.

47. YadavM, LouvetC, DaviniD, GardnerJM, Martinez-LlordellaM, et al. (2012) Neuropilin-1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo. J Exp Med 209: 1713–1719, 1713-1722, S1711-1719.

48. KhanAI, HoriiY, TiuriaR, SatoY, NawaY (1993) Mucosal mast cells and the expulsive mechanisms of mice against Strongyloides venezuelensis. Int J Parasitol 23: 551–555.

49. ReynoldsDS, StevensRL, LaneWS, CarrMH, AustenKF, et al. (1990) Different mouse mast cell populations express various combinations of at least six distinct mast cell serine proteases. Proc Natl Acad Sci U S A 87: 3230–3234.

50. TittelAP, HeuserC, OhligerC, LlantoC, YonaS, et al. (2012) Functionally relevant neutrophilia in CD11c diphtheria toxin receptor transgenic mice. Nature methods 9: 385–390.

51. MachadoER, CarlosD, LourencoEV, SorgiCA, SilvaEV, et al. (2009) Counterregulation of Th2 immunity by interleukin 12 reduces host defenses against Strongyloides venezuelensis infection. Microbes Infect 11: 571–578.

52. Bonne-AnneeS, HessJA, AbrahamD (2011) Innate and adaptive immunity to the nematode Strongyloides stercoralis in a mouse model. Immunologic research 51: 205–214.

53. LantzCS, BoesigerJ, SongCH, MachN, KobayashiT, et al. (1998) Role for interleukin-3 in mast-cell and basophil development and in immunity to parasites. Nature 392: 90–93.

54. AbeT, SugayaH, IshidaK, KhanWI, TasdemirI, et al. (1993) Intestinal protection against Strongyloides ratti and mastocytosis induced by administration of interleukin-3 in mice. Immunology 80: 116–121.

55. NoelleRJ, NowakEC (2010) Cellular sources and immune functions of interleukin-9. Nature reviews Immunology 10: 683–687.

56. TownsendJM, FallonGP, MatthewsJD, SmithP, JolinEH, et al. (2000) IL-9-deficient mice establish fundamental roles for IL-9 in pulmonary mastocytosis and goblet cell hyperplasia but not T cell development. Immunity 13: 573–583.

57. FaulknerH, RenauldJC, Van SnickJ, GrencisRK (1998) Interleukin-9 enhances resistance to the intestinal nematode Trichuris muris. Infection and immunity 66: 3832–3840.

58. FaulknerH, HumphreysN, RenauldJC, Van SnickJ, GrencisR (1997) Interleukin-9 is involved in host protective immunity to intestinal nematode infection. European Journal of Immunology 27: 2536–2540.

59. RichardM, GrencisRK, HumphreysNE, RenauldJC, Van SnickJ (2000) Anti-IL-9 vaccination prevents worm expulsion and blood eosinophilia in Trichuris muris-infected mice. Proc Natl Acad Sci U S A 97: 767–772.

60. KhanWI, RichardM, AkihoH, BlennerhassetPA, HumphreysNE, et al. (2003) Modulation of intestinal muscle contraction by interleukin-9 (IL-9) or IL-9 neutralization: correlation with worm expulsion in murine nematode infections. Infection and immunity 71: 2430–2438.

61. FeyerabendTB, WeiserA, TietzA, StassenM, HarrisN, et al. (2011) Cre-mediated cell ablation contests mast cell contribution in models of antibody- and T cell-mediated autoimmunity. Immunity 35: 832–844.

62. KatzHR, AustenKF (2011) Mast cell deficiency, a game of kit and mouse. Immunity 35: 668–670.

63. MichelA, SchulerA, FriedrichP, DonerF, BoppT, et al. (2013) Mast cell-deficient Kit(W-sh) “Sash” mutant mice display aberrant myelopoiesis leading to the accumulation of splenocytes that act as myeloid-derived suppressor cells. Journal of Immunology 190: 5534–5544.

64. AntsiferovaM, MartinC, HuberM, FeyerabendTB, ForsterA, et al. (2013) Mast Cells Are Dispensable for Normal and Activin-Promoted Wound Healing and Skin Carcinogenesis. Journal of Immunology 191: 6147–55.

65. Gomez-PinillaPJFG, GiovangiulioMD, StakenborgN, NemethovaA, de VriesA, et al. (2014) Mast cells play no role in the pathogenesis of postoperative ileus induced by intestinal manipulation. PLOS One in press.

66. GriG, PiconeseS, FrossiB, ManfroiV, MerluzziS, et al. (2008) CD4+CD25+ regulatory T cells suppress mast cell degranulation and allergic responses through OX40-OX40L interaction. Immunity 29: 771–781.

67. EllerK, WolfD, HuberJM, MetzM, MayerG, et al. (2011) IL-9 production by regulatory T cells recruits mast cells that are essential for regulatory T cell-induced immune suppression. Journal of Immunology 186: 83–91.

68. LuLF, LindEF, GondekDC, BennettKA, GleesonMW, et al. (2006) Mast cells are essential intermediaries in regulatory T-cell tolerance. Nature 442: 997–1002.

69. VeldhoenM, UyttenhoveC, van SnickJ, HelmbyH, WestendorfA, et al. (2008) Transforming growth factor-beta ‘reprograms’ the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat Immunol 9: 1341–1346.

70. WilhelmC, HirotaK, StieglitzB, Van SnickJ, TolainiM, et al. (2011) An IL-9 fate reporter demonstrates the induction of an innate IL-9 response in lung inflammation. Nat Immunol 12: 1071–1077.

71. GodfraindC, LouahedJ, FaulknerH, VinkA, WarnierG, et al. (1998) Intraepithelial infiltration by mast cells with both connective tissue-type and mucosal-type characteristics in gut, trachea, and kidneys of IL-9 transgenic mice. Journal of Immunology 160: 3989–3996.

72. ChenX, OppenheimJJ, HowardOM (2005) BALB/c mice have more CD4+CD25+ T regulatory cells and show greater susceptibility to suppression of their CD4+CD25− responder T cells than C57BL/6 mice. J Leukoc Biol 78: 114–121.

73. MorampudiV, De CraeyeS, Le MoineA, DetienneS, BraunMY, et al. (2011) Partial depletion of CD4(+)CD25(+)Foxp3(+) T regulatory cells significantly increases morbidity during acute phase Toxoplasma gondii infection in resistant BALB/c mice. Microbes and infection/Institut Pasteur 13: 394–404.

74. PaulaMO, FonsecaDM, WowkPF, GembreAF, FedattoPF, et al. (2011) Host genetic background affects regulatory T-cell activity that influences the magnitude of cellular immune response against Mycobacterium tuberculosis. Immunol Cell Biol 89: 526–534.

75. ForbesEE, GroschwitzK, AboniaJP, BrandtEB, CohenE, et al. (2008) IL-9- and mast cell-mediated intestinal permeability predisposes to oral antigen hypersensitivity. J Exp Med 205: 897–913.

76. BrandtEB, StraitRT, HershkoD, WangQ, MuntelEE, et al. (2003) Mast cells are required for experimental oral allergen-induced diarrhea. The Journal of clinical investigation 112: 1666–1677.

77. NouirNB, EschbachML, PiedaventM, OsterlohA, KingsleyMT, et al. (2012) Vaccination with Strongyloides ratti heat shock protein 60 increases susceptibility to challenge infection by induction of Th1 response. Vaccine 30: 862–871.

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Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

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