Follicular Helper T Cells Promote Liver Pathology in Mice during Infection

English version České info

Schistosomiasis is a chronic helminthic disease that affects approximately 200 million people. After S. japonicum infection, parasite eggs are trapped in host liver and granulomas are induced to form around eggs. Severe granuloma subsequently results in serious liver fibrosis and circulatory impairment chronically. It is important to fully elucidate the mechanism of the granuloma formation. Here, we show that Tfh cells play a novel role of promoting the hepatic granuloma formation and liver injury, and identified a novel function of macrophages in Tfh cells induction in S. japonicum-infected mouse model. In addition, we show that the generation of Tfh cells driven by macrophages is cell–cell contact dependent and regulated by CD40-CD40L signaling. Our findings revealed a novel role and mechanism of macrophages in Tfh cell generation and the liver pathogenesis in S. japonicum-infected mouse model.

Vyšlo v časopise: Follicular Helper T Cells Promote Liver Pathology in Mice during Infection. PLoS Pathog 10(5): e32767. doi:10.1371/journal.ppat.1004097
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004097

Souhrn

Zdroje

1. RossAG, BartleyPB, SleighAC, OldsGR, LiY, et al. (2002) Schistosomiasis. N Engl J Med 346 : 1212–1220.

2. GryseelsB, PolmanK, ClerinxJ, KestensL (2006) Human schistosomiasis. Lancet 368 : 1106–1118.

3. PearceEJ, MacDonaldAS (2002) The immunobiology of schistosomiasis. Nat Rev Immunol 2 : 499–511.

4. KaplanMH, WhitfieldJR, BorosDL, GrusbyMJ (1998) Th2 cells are required for the Schistosoma mansoni egg-induced granulomatous response. J Immunol 160 : 1850–1856.

5. RutitzkyLI, StadeckerMJ (2011) Exacerbated egg-induced immunopathology in murine Schistosoma mansoni infection is primarily mediated by IL-17 and restrained by IFN-gamma. Eur J Immunol 41 : 2677–2687.

6. WenX, HeL, ChiY, ZhouS, HoellwarthJ, et al. (2011) Dynamics of Th17 cells and their role in Schistosoma japonicum infection in C57BL/6 mice. PLoS Negl Trop Dis 5: e1399.

7. SinghKP, GerardHC, HudsonAP, ReddyTR, BorosDL (2005) Retroviral Foxp3 gene transfer ameliorates liver granuloma pathology in Schistosoma mansoni infected mice. Immunology 114 : 410–417.

8. NurievaRI, ChungY, HwangD, YangXO, KangHS, et al. (2008) Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity 29 : 138–149.

9. MaCS, DeenickEK, BattenM, TangyeSG (2012) The origins, function, and regulation of T follicular helper cells. J Exp Med 209 : 1241–1253.

10. KingC, TangyeSG, MackayCR (2008) T follicular helper (TFH) cells in normal and dysregulated immune responses. Annu Rev Immunol 26 : 741–766.

11. LiuX, YanX, ZhongB, NurievaRI, WangA, et al. (2012) Bcl6 expression specifies the T follicular helper cell program in vivo. J Exp Med 209 : 1841–1852, S1841–1824.

12. Good-JacobsonKL, SzumilasCG, ChenL, SharpeAH, TomaykoMM, et al. (2010) PD-1 regulates germinal center B cell survival and the formation and affinity of long-lived plasma cells. Nat Immunol 11 : 535–542.

13. CannonsJL, QiH, LuKT, DuttaM, Gomez-RodriguezJ, et al. (2010) Optimal germinal center responses require a multistage T cell:B cell adhesion process involving integrins, SLAM-associated protein, and CD84. Immunity 32 : 253–265.

14. LintermanMA, RigbyRJ, WongRK, YuD, BrinkR, et al. (2009) Follicular helper T cells are required for systemic autoimmunity. J Exp Med 206 : 561–576.

15. AokiN, KidoM, IwamotoS, NishiuraH, MaruokaR, et al. (2011) Dysregulated Generation of Follicular Helper T Cells in the Spleen Triggers Fatal Autoimmune Hepatitis in Mice. Gastroenterology 140 : 1322–1333.e1325.

16. SimpsonN, GatenbyPA, WilsonA, MalikS, FulcherDA, et al. (2010) Expansion of circulating T cells resembling follicular helper T cells is a fixed phenotype that identifies a subset of severe systemic lupus erythematosus. Arthritis Rheum 62 : 234–244.

17. ReinhardtRL, LiangHE, LocksleyRM (2009) Cytokine-secreting follicular T cells shape the antibody repertoire. Nat Immunol 10 : 385–393.

18. KingIL, MohrsM (2009) IL-4-producing CD4+ T cells in reactive lymph nodes during helminth infection are T follicular helper cells. Journal of Experimental Medicine 206 : 1001–1007.

19. HamsE, McCarronMJ, AmuS, YagitaH, AzumaM, et al. (2011) Blockade of B7-H1 (programmed death ligand 1) enhances humoral immunity by positively regulating the generation of T follicular helper cells. J Immunol 186 : 5648–5655.

20. ZaretskyAG, TaylorJJ, KingIL, MarshallFA, MohrsM, et al. (2009) T follicular helper cells differentiate from Th2 cells in response to helminth antigens. J Exp Med 206 : 991–999.

21. JohnstonRJ, PoholekAC, DiToroD, YusufI, EtoD, et al. (2009) Bcl6 and Blimp-1 Are Reciprocal and Antagonistic Regulators of T Follicular Helper Cell Differentiation. Science 325 : 1006–1010.

22. HaynesNM, AllenCD, LesleyR, AnselKM, KilleenN, et al. (2007) Role of CXCR5 and CCR7 in follicular Th cell positioning and appearance of a programmed cell death gene-1high germinal center-associated subpopulation. J Immunol 179 : 5099–5108.

23. DeenickEK, MaCS, BrinkR, TangyeSG (2011) Regulation of T follicular helper cell formation and function by antigen presenting cells. Curr Opin Immunol 23 : 111–118.

24. QiH, CannonsJL, KlauschenF, SchwartzbergPL, GermainRN (2008) SAP-controlled T-B cell interactions underlie germinal centre formation. Nature 455 : 764–769.

25. EbertLM, HornMP, LangAB, MoserB (2004) B cells alter the phenotype and function of follicular-homing CXCR5+ T cells. Eur J Immunol 34 : 3562–3571.

26. DeenickEK, ChanA, MaCS, GattoD, SchwartzbergPL, et al. (2010) Follicular Helper T Cell Differentiation Requires Continuous Antigen Presentation that Is Independent of Unique B Cell Signaling. Immunity 33 : 241–253.

27. FaheyLM, WilsonEB, ElsaesserH, FistonichCD, McGavernDB, et al. (2011) Viral persistence redirects CD4 T cell differentiation toward T follicular helper cells. J Exp Med 208 : 987–999.

28. YooJK, FishEN, BracialeTJ (2012) LAPCs promote follicular helper T cell differentiation of Ag-primed CD4+ T cells during respiratory virus infection. J Exp Med 209 : 1853–1867.

29. PelletierN, McHeyzer-WilliamsLJ, WongKA, UrichE, FazilleauN, et al. (2010) Plasma cells negatively regulate the follicular helper T cell program. Nat Immunol 11 : 1110–1118.

30. WilsonMS, Mentink-KaneMM, PesceJT, RamalingamTR, ThompsonR, et al. (2007) Immunopathology of schistosomiasis. Immunol Cell Biol 85 : 148–154.

31. BatallerR, BrennerDA (2005) Liver fibrosis. J Clin Invest 115 : 209–218.

32. CrottyS (2011) Follicular helper CD4 T cells (TFH). Annu Rev Immunol 29 : 621–663.

33. ChoiYS, KageyamaR, EtoD, EscobarTC, JohnstonRJ, et al. (2011) ICOS receptor instructs T follicular helper cell versus effector cell differentiation via induction of the transcriptional repressor Bcl6. Immunity 34 : 932–946.

34. GrimbacherB, HutloffA, SchlesierM, GlockerE, WarnatzK, et al. (2003) Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency. Nat Immunol 4 : 261–268.

35. WarnatzK, BossallerL, SalzerU, Skrabl-BaumgartnerA, SchwingerW, et al. (2006) Human ICOS deficiency abrogates the germinal center reaction and provides a monogenic model for common variable immunodeficiency. Blood 107 : 3045–3052.

36. ElliottDE (1996) Methods Used to Study Immunoregulation of Schistosome Egg Granulomas. Methods 9 : 255–267.

37. DesmedtM, RottiersP, DoomsH, FiersW, GrootenJ (1998) Macrophages induce cellular immunity by activating Th1 cell responses and suppressing Th2 cell responses. J Immunol 160 : 5300–5308.

38. MoserM (2001) Regulation of Th1/Th2 development by antigen-presenting cells in vivo. Immunobiology 204 : 551–557.

39. KrausgruberT, BlazekK, SmallieT, AlzabinS, LockstoneH, et al. (2011) IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses. Nat Immunol 12 : 231–238.

40. DenningTL, NorrisBA, Medina-ContrerasO, ManicassamyS, GeemD, et al. (2011) Functional specializations of intestinal dendritic cell and macrophage subsets that control Th17 and regulatory T cell responses are dependent on the T cell/APC ratio, source of mouse strain, and regional localization. J Immunol 187 : 733–747.

41. KraaijMD, SavageND, van der KooijSW, KoekkoekK, WangJ, et al. (2010) Induction of regulatory T cells by macrophages is dependent on production of reactive oxygen species. Proceedings of the National Academy of Sciences of the United States of America 107 : 17686–17691.

42. SavageND, de BoerT, WalburgKV, JoostenSA, van MeijgaardenK, et al. (2008) Human anti-inflammatory macrophages induce Foxp3+ GITR+ CD25+ regulatory T cells, which suppress via membrane-bound TGFbeta-1. Journal of immunology 181 : 2220–2226.

43. LinHH, FaunceDE, StaceyM, TerajewiczA, NakamuraT, et al. (2005) The macrophage F4/80 receptor is required for the induction of antigen-specific efferent regulatory T cells in peripheral tolerance. The Journal of experimental medicine 201 : 1615–1625.

44. MelnicoffMJ, HoranPK, BreslinEW, MorahanPS (1988) Maintenance of peritoneal macrophages in the steady state. J Leukoc Biol 44 : 367–375.

45. BellinganGJ, CaldwellH, HowieSE, DransfieldI, HaslettC (1996) In vivo fate of the inflammatory macrophage during the resolution of inflammation: inflammatory macrophages do not die locally, but emigrate to the draining lymph nodes. J Immunol 157 : 2577–2585.

46. RosenH, GordonS (1990) Adoptive transfer of fluorescence-labeled cells shows that resident peritoneal macrophages are able to migrate into specialized lymphoid organs and inflammatory sites in the mouse. Eur J Immunol 20 : 1251–1258.

47. HuH, WuX, JinW, ChangM, ChengX, et al. (2011) Noncanonical NF-kappaB regulates inducible costimulator (ICOS) ligand expression and T follicular helper cell development. Proc Natl Acad Sci U S A 108 : 12827–12832.

48. HernandezHJ, WangY, StadeckerMJ (1997) In infection with Schistosoma mansoni, B cells are required for T helper type 2 cell responses but not for granuloma formation. J Immunol 158 : 4832–4837.

49. JiF, LiuZ, CaoJ, LiN, ZuoJ, et al. (2008) B cell response is required for granuloma formation in the early infection of Schistosoma japonicum. PLoS One 3: e1724.

50. JankovicD, CheeverAW, KullbergMC, WynnTA, YapG, et al. (1998) CD4+ T cell-mediated granulomatous pathology in schistosomiasis is downregulated by a B cell-dependent mechanism requiring Fc receptor signaling. J Exp Med 187 : 619–629.

51. PesceJ, KaviratneM, RamalingamTR, ThompsonRW, UrbanJFJr, et al. (2006) The IL-21 receptor augments Th2 effector function and alternative macrophage activation. J Clin Invest 116 : 2044–2055.

52. WursterAL, RodgersVL, SatoskarAR, WhittersMJ, YoungDA, et al. (2002) Interleukin 21 Is a T Helper (Th) Cell 2 Cytokine that Specifically Inhibits the Differentiation of Naive Th Cells into Interferon -producing Th1 Cells. Journal of Experimental Medicine 196 : 969–977.

53. LuthjeK, KalliesA, ShimohakamadaY, GTTB, LightA, et al. (2012) The development and fate of follicular helper T cells defined by an IL-21 reporter mouse. Nat Immunol 13 : 491–498.

54. RothenbergME, HoganSP (2006) The eosinophil. Annual Review of Immunology 24 : 147–174.

55. LuKT, KannoY, CannonsJL, HandonR, BibleP, et al. (2011) Functional and epigenetic studies reveal multistep differentiation and plasticity of in vitro-generated and in vivo-derived follicular T helper cells. Immunity 35 : 622–632.

56. BauquetAT, JinH, PatersonAM, MitsdoerfferM, HoIC, et al. (2009) The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH-17 cells. Nat Immunol 10 : 167–175.

57. FengJ, LuL, HuaC, QinL, ZhaoP, et al. (2011) High Frequency of CD4CXCR5 TFH Cells in Patients with Immune-Active Chronic Hepatitis B. PLoS One 6: e21698.

58. HutloffA, BuchnerK, ReiterK, BaeldeHJ, OdendahlM, et al. (2004) Involvement of inducible costimulator in the exaggerated memory B cell and plasma cell generation in systemic lupus erythematosus. Arthritis Rheum 50 : 3211–3220.

59. VinuesaCG, SanzI, CookMC (2009) Dysregulation of germinal centres in autoimmune disease. Nature Reviews Immunology 9 : 845–857.

60. TripodoC, PettaS, GuarnottaC, PipitoneR, CabibiD, et al. (2012) Liver follicular helper T-cells predict the achievement of virological response following interferon-based treatment in HCV-infected patients. Antivir Ther 17 : 111–118.

61. CucakH, YrlidU, ReizisB, KalinkeU, Johansson-LindbomB (2009) Type I interferon signaling in dendritic cells stimulates the development of lymph-node-resident T follicular helper cells. Immunity 31 : 491–501.

62. MebiusRE, KraalG (2005) Structure and function of the spleen. Nature Reviews Immunology 5 : 606–616.

63. KreiderT, AnthonyRM, UrbanJFJr, GauseWC (2007) Alternatively activated macrophages in helminth infections. Curr Opin Immunol 19 : 448–453.

64. BroadhurstMJ, LeungJM, LimKC, GirgisNM, GundraUM, et al. (2012) Upregulation of retinal dehydrogenase 2 in alternatively activated macrophages during retinoid-dependent type-2 immunity to helminth infection in mice. PLoS Pathog 8: e1002883.

65. CrispeIN (2009) The liver as a lymphoid organ. Annu Rev Immunol 27 : 147–163.

66. WherryEJ (2011) T cell exhaustion. Nat Immunol 12 : 492–499.

67. ButlerNS, MoebiusJ, PeweLL, TraoreB, DoumboOK, et al. (2012) Therapeutic blockade of PD-L1 and LAG-3 rapidly clears established blood-stage Plasmodium infection. Nat Immunol 13 : 188–195.

68. WherryEJ, HaSJ, KaechSM, HainingWN, SarkarS, et al. (2007) Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27 : 670–684.

69. OdegardJM, MarksBR, DiPlacidoLD, PoholekAC, KonoDH, et al. (2008) ICOS-dependent extrafollicular helper T cells elicit IgG production via IL-21 in systemic autoimmunity. Journal of Experimental Medicine 205 : 2873–2886.

70. GrewalIS, XuJ, FlavellRA (1995) Impairment of antigen-specific T-cell priming in mice lacking CD40 ligand. Nature 378 : 617–620.

71. van EssenD, KikutaniH, GrayD (1995) CD40 ligand-transduced co-stimulation of T cells in the development of helper function. Nature 378 : 620–623.

72. MetwaliA, ElliottD, MathewR, BlumA, WeinstockJV (1993) IL-2 contributes to the IL-5 response in granulomas from mice infected with Schistosoma mansoni. J Immunol 150 : 536–542.

73. RakaszE, BlumAM, MetwaliA, ElliottDE, LiJ, et al. (1998) Localization and regulation of IFN-gamma production within the granulomas of murine schistosomiasis in IL-4-deficient and control mice. J Immunol 160 : 4994–4999.

74. FairfaxKC, EvertsB, SmithAM, PearceEJ (2013) Regulation of the development of the hepatic B cell compartment during Schistosoma mansoni infection. J Immunol 191 : 4202–4210.

75. KeladaS, SethupathyP, OkoyeIS, KistasisE, CziesoS, et al. (2013) miR-182 and miR-10a are key regulators of Treg specialisation and stability during Schistosome and Leishmania-associated inflammation. PLoS Pathog 9: e1003451.

76. IkedaY, MurakamiA, FujimuraY, TachibanaH, YamadaK, et al. (2007) Aggregated ursolic acid, a natural triterpenoid, induces IL-1beta release from murine peritoneal macrophages: role of CD36. Journal of immunology 178 : 4854–4864.

77. NawijnMC, DingjanGM, FerreiraR, LambrechtBN, KarisA, et al. (2001) Enforced expression of GATA-3 in transgenic mice inhibits Th1 differentiation and induces the formation of a T1/ST2-expressing Th2-committed T cell compartment in vivo. J Immunol 167 : 724–732.

78. KropfP, BickleQ, HerathS, KlemenzR, MullerI (2002) Organ-specific distribution of CD4+ T1/ST2+ Th2 cells in Leishmania major infection. Eur J Immunol 32 : 2450–2459.

79. PotterJJ, Rennie-TankesleyL, MezeyE (2003) Influence of leptin in the development of hepatic fibrosis produced in mice by Schistosoma mansoni infection and by chronic carbon tetrachloride administration. J Hepatol 38 : 281–288.