Abortive T Follicular Helper Development Is Associated with a Defective Humoral Response in -Infected Macaques

English version České info

We introduced a non-human primate model for visceral leishmaniasis by intravenous injection of L. infantum promastigotes in rhesus macaques and followed the animals for a period of eight months. In this model, parasites dock to the liver and spleen shortly after inoculation and remain in these visceral compartments during all the acute phase of infection. However, at the chronic phase, additional body locations appeared colonized (lymph nodes, bone marrow). During the acute phase, a Th1-polarized CD4 T cell response develops in the spleen, but, and concomitant with parasite growth, it waned at the chronic phase. Furthermore, we observed the acute expansion of a splenic T follicular helper (Tfh) cell population, a CD4+ T cell subset specialized to assist B cells in the production of antigen-specific antibody. These cells were localized in close association with B cell follicles but, interestingly, the Tfh population is lost at the chronic phase. Nevertheless, there was a close association between the development of Tfh cells and the differentiation of B cells that produce L. infantum-specific IgG. Thus, our results suggest that Tfh cells are important in instructing B cells to produce parasite-specific antibodies during VL, but their abortive differentiation precludes the continuous production of specific-IgG.

Vyšlo v časopise: Abortive T Follicular Helper Development Is Associated with a Defective Humoral Response in -Infected Macaques. PLoS Pathog 10(4): e32767. doi:10.1371/journal.ppat.1004096
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004096

Souhrn

Zdroje

1. MurrayHW, BermanJD, DaviesCR, SaraviaNG (2005) Advances in leishmaniasis. Lancet 366: 1561–1577.

2. KayeP, ScottP (2011) Leishmaniasis: complexity at the host-pathogen interface. Nat Rev Microbiol 9: 604–615.

3. NylenS, SacksD (2007) Interleukin-10 and the pathogenesis of human visceral leishmaniasis. Trends Immunol 28: 378–384.

4. BanerjeeR, KumarS, SenA, MookerjeeA, MukherjeeP, et al. (2011) TGF-beta-regulated tyrosine phosphatases induce lymphocyte apoptosis in Leishmania donovani-infected hamsters. Immunol Cell Biol 89: 466–474.

5. NietoA, Dominguez-BernalG, OrdenJA, De La FuenteR, Madrid-ElenaN, et al. (2011) Mechanisms of resistance and susceptibility to experimental visceral leishmaniosis: BALB/c mouse versus syrian hamster model. Vet Res 42: 39.

6. KenneyRT, SacksDL, GamAA, MurrayHW, SundarS (1998) Splenic cytokine responses in Indian kala-azar before and after treatment. J Infect Dis 177: 815–818.

7. KarpCL, el-SafiSH, WynnTA, SattiMM, KordofaniAM, et al. (1993) In vivo cytokine profiles in patients with kala-azar. Marked elevation of both interleukin-10 and interferon-gamma. J Clin Invest 91: 1644–1648.

8. GotoH, PriantiMG (2009) Immunoactivation and immunopathogeny during active visceral leishmaniasis. Rev Inst Med Trop Sao Paulo 51: 241–246.

9. McCallLI, ZhangWW, MatlashewskiG (2013) Determinants for the development of visceral leishmaniasis disease. PLoS Pathog 9: e1003053.

10. BrenchleyJM, VintonC, TabbB, HaoXP, ConnickE, et al. (2012) Differential infection patterns of CD4+ T cells and lymphoid tissue viral burden distinguish progressive and nonprogressive lentiviral infections. Blood 120: 4172–4181.

11. HurtrelB, PetitF, ArnoultD, Muller-TrutwinM, SilvestriG, et al. (2005) Apoptosis in SIV infection. Cell Death Differ 12 Suppl 1: 979–990.

12. MicciL, CervasiB, EndeZS, IrieleRI, Reyes-AvilesE, et al. (2012) Paucity of IL-21-producing CD4(+) T cells is associated with Th17 cell depletion in SIV infection of rhesus macaques. Blood 120: 3925–3935.

13. PorrozziR, PereiraMS, TevaA, VolpiniAC, PintoMA, et al. (2006) Leishmania infantum-induced primary and challenge infections in rhesus monkeys (Macaca mulatta): a primate model for visceral leishmaniasis. Trans R Soc Trop Med Hyg 100: 926–937.

14. GrimaldiGJr (2008) The utility of rhesus monkey (Macaca mulatta) and other non-human primate models for preclinical testing of Leishmania candidate vaccines. Mem Inst Oswaldo Cruz 103: 629–644.

15. EvansTG, KrugEC, WilsonME, VasconcelosAW, de AlencarJE, et al. (1989) Evaluation of antibody responses in American visceral leishmaniasis by ELISA and immunoblot. Mem Inst Oswaldo Cruz 84: 157–166.

16. SmeltSC, CotterellSE, EngwerdaCR, KayePM (2000) B cell-deficient mice are highly resistant to Leishmania donovani infection, but develop neutrophil-mediated tissue pathology. J Immunol 164: 3681–3688.

17. DeakE, JayakumarA, ChoKW, Goldsmith-PestanaK, DondjiB, et al. (2010) Murine visceral leishmaniasis: IgM and polyclonal B-cell activation lead to disease exacerbation. Eur J Immunol 40: 1355–1368.

18. BankotiR, GuptaK, LevchenkoA, StagerS (2012) Marginal zone B cells regulate antigen-specific T cell responses during infection. J Immunol 188: 3961–3971.

19. ScottP, NatovitzP, SherA (1986) B lymphocytes are required for the generation of T cells that mediate healing of cutaneous leishmaniasis. J Immunol 137: 1017–1021.

20. WoelbingF, KostkaSL, MoelleK, BelkaidY, SunderkoetterC, et al. (2006) Uptake of Leishmania major by dendritic cells is mediated by Fcgamma receptors and facilitates acquisition of protective immunity. J Exp Med 203: 177–188.

21. ZotosD, TarlintonDM (2012) Determining germinal centre B cell fate. Trends Immunol 33: 281–288.

22. LutherSA, MaillardI, LuthiF, ScarpellinoL, DiggelmannH, et al. (1997) Early neutralizing antibody response against mouse mammary tumor virus: critical role of viral infection and superantigen-reactive T cells. J Immunol 159: 2807–2814.

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

24. OnabajoOO, GeorgeJ, LewisMG, MattapallilJJ (2013) Rhesus macaque lymph node PD-1(hi)CD4+ T cells express high levels of CXCR5 and IL-21 and display a CCR7(lo)ICOS+Bcl6+ T-follicular helper (Tfh) cell phenotype. PLoS One 8: e59758.

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

26. MontesCL, Acosta-RodriguezEV, MerinoMC, BermejoDA, GruppiA (2007) Polyclonal B cell activation in infections: infectious agents' devilry or defense mechanism of the host? J Leukoc Biol 82: 1027–1032.

27. MaryC, FarautF, LascombeL, DumonH (2004) Quantification of Leishmania infantum DNA by a real-time PCR assay with high sensitivity. J Clin Microbiol 42: 5249–5255.

28. KrammerPH, ArnoldR, LavrikIN (2007) Life and death in peripheral T cells. Nat Rev Immunol 7: 532–542.

29. PaganAJ, PetersNC, DebrabantA, Ribeiro-GomesF, PepperM, et al. (2012) Tracking antigen-specific CD4(+) T cells throughout the course of chronic Leishmania major infection in resistant mice. Eur J Immunol 43(2): 427–38.

30. AndersonCF, OukkaM, KuchrooVJ, SacksD (2007) CD4(+)CD25(−)Foxp3(−) Th1 cells are the source of IL-10-mediated immune suppression in chronic cutaneous leishmaniasis. J Exp Med 204: 285–297.

31. NylenS, MauryaR, EidsmoL, ManandharKD, SundarS, et al. (2007) Splenic accumulation of IL-10 mRNA in T cells distinct from CD4+CD25+ (Foxp3) regulatory T cells in human visceral leishmaniasis. J Exp Med 204: 805–817.

32. OwensBM, BeattieL, MooreJW, BrownN, MannJL, et al. (2012) IL-10-producing Th1 cells and disease progression are regulated by distinct CD11c(+) cell populations during visceral leishmaniasis. PLoS Pathog 8: e1002827.

33. StagerS, MaroofA, ZubairiS, SanosSL, KopfM, et al. (2006) Distinct roles for IL-6 and IL-12p40 in mediating protection against Leishmania donovani and the expansion of IL-10+ CD4+ T cells. Eur J Immunol 36: 1764–1771.

34. MebiusRE, KraalG (2005) Structure and function of the spleen. Nat Rev Immunol 5: 606–616.

35. MoirS, FauciAS (2009) B cells in HIV infection and disease. Nat Rev Immunol 9: 235–245.

36. TitanjiK, VeluV, ChennareddiL, Vijay-KumarM, GewirtzAT, et al. (2010) Acute depletion of activated memory B cells involves the PD-1 pathway in rapidly progressing SIV-infected macaques. J Clin Invest 120: 3878–3890.

37. CaldwellCW, MartyLM, FeldbushTL (1991) Expression of the low Mr isoform of CD45 (CD45RO) in B-cell non-Hodgkin's lymphomas. Clin Immunol Immunopathol 58: 377–384.

38. JacksonSM, HarpN, PatelD, ZhangJ, WillsonS, et al. (2007) CD45RO enriches for activated, highly mutated human germinal center B cells. Blood 110: 3917–3925.

39. BerkowskaMA, DriessenGJ, BikosV, Grosserichter-WagenerC, StamatopoulosK, et al. (2011) Human memory B cells originate from three distinct germinal center-dependent and -independent maturation pathways. Blood 118: 2150–2158.

40. CumontMC, DiopO, VaslinB, ElbimC, ViolletL, et al. (2008) Early divergence in lymphoid tissue apoptosis between pathogenic and nonpathogenic simian immunodeficiency virus infections of nonhuman primates. J Virol 82: 1175–1184.

41. EngwerdaCR, KayePM (2000) Organ-specific immune responses associated with infectious disease. Immunol Today 21: 73–78.

42. EidsmoL, WoldayD, BerheN, SabriF, SattiI, et al. (2002) Alteration of Fas and Fas ligand expression during human visceral leishmaniasis. Clin Exp Immunol 130: 307–313.

43. HeinzelFP, SadickMD, MuthaSS, LocksleyRM (1991) Production of interferon gamma, interleukin 2, interleukin 4, and interleukin 10 by CD4+ lymphocytes in vivo during healing and progressive murine leishmaniasis. Proc Natl Acad Sci U S A 88: 7011–7015.

44. GhalibHW, PiuvezamMR, SkeikyYA, SiddigM, HashimFA, et al. (1993) Interleukin 10 production correlates with pathology in human Leishmania donovani infections. J Clin Invest 92: 324–329.

45. O'GarraA, VieiraP (2007) T(H)1 cells control themselves by producing interleukin-10. Nat Rev Immunol 7: 425–428.

46. ColleJH, Truffa-BachiP, ChedidL, ModabberF (1983) Lack of general immunosuppression during visceral Leishmania tropica infection in BALB/c mice: augmented antibody response to thymus-independent antigens and polyclonal activation. J Immunol 131: 1492–1495.

47. Campos-NetoA, Bunn-MorenoMM (1982) Polyclonal B cell activation in hamsters infected with parasites of the genus Leishmania. Infect Immun 38: 871–876.

48. Agenor Araujo Lima VerdeF, Araujo Lima VerdeF, De Francesco DaherE, Martins Dos SantosG, Saboia NetoA, et al. (2009) Renal tubular dysfunction in human visceral leishmaniasis (Kala-azar). Clin Nephrol 71: 492–500.

49. LuthjeK, KalliesA, ShimohakamadaY, BelzGT, 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.

50. JonesJL, PhuahCL, CoxAL, ThompsonSA, BanM, et al. (2009) IL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H). J Clin Invest 119: 2052–2061.

51. LouzirH, Belal-KacemiL, SassiA, LaouiniD, Ben IsmailR, et al. (1994) Natural autoantibodies, IgG antibodies to tetanus toxoid and CD5+ B cells in patients with Mediterranean visceral leishmaniasis. The Leishmania Study Group. Clin Exp Immunol 95: 479–484.

52. ArgovS, JaffeCL, KruppM, SlorH, ShoenfeldY (1989) Autoantibody production by patients infected with Leishmania. Clin Exp Immunol 76: 190–197.

53. LeeSK, RigbyRJ, ZotosD, TsaiLM, KawamotoS, et al. (2011) B cell priming for extrafollicular antibody responses requires Bcl-6 expression by T cells. J Exp Med 208: 1377–1388.

54. KerfootSM, YaariG, PatelJR, JohnsonKL, GonzalezDG, et al. (2011) Germinal center B cell and T follicular helper cell development initiates in the interfollicular zone. Immunity 34: 947–960.

55. 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.

56. Cordeiro-Da-SilvaA, BorgesMC, GuilvardE, OuaissiA (2001) Dual role of the Leishmania major ribosomal protein S3a homologue in regulation of T- and B-cell activation. Infect Immun 69: 6588–6596.

57. RicoAI, GironesN, FresnoM, AlonsoC, RequenaJM (2002) The heat shock proteins, Hsp70 and Hsp83, of Leishmania infantum are mitogens for mouse B cells. Cell Stress Chaperones 7: 339–346.

58. BermejoDA, Amezcua VeselyMC, KhanM, Acosta RodriguezEV, MontesCL, et al. (2011) Trypanosoma cruzi infection induces a massive extrafollicular and follicular splenic B-cell response which is a high source of non-parasite-specific antibodies. Immunology 132: 123–133.

59. XuY, WeatherallC, BaileyM, AlcantaraS, De RoseR, et al. (2013) SIV Infects Follicular Helper CD4 T cells in Lymphoid Tissues During Pathogenic Infection of Pigtail Macaques. J Virol 87: 3760–73.

60. PetrovasC, YamamotoT, GernerMY, BoswellKL, WlokaK, et al. (2012) CD4 T follicular helper cell dynamics during SIV infection. J Clin Invest 122: 3281–3294.

61. LindqvistM, van LunzenJ, SoghoianDZ, KuhlBD, RanasingheS, et al. (2012) Expansion of HIV-specific T follicular helper cells in chronic HIV infection. J Clin Invest 122: 3271–3280.

62. Chacon-SalinasR, Limon-FloresAY, Chavez-BlancoAD, Gonzalez-EstradaA, UllrichSE (2011) Mast cell-derived IL-10 suppresses germinal center formation by affecting T follicular helper cell function. J Immunol 186: 25–31.

63. RoussetF, GarciaE, DefranceT, PeronneC, VezzioN, et al. (1992) Interleukin 10 is a potent growth and differentiation factor for activated human B lymphocytes. Proc Natl Acad Sci U S A 89: 1890–1893.

64. SilvestreR, Cordeiro-Da-SilvaA, SantaremN, VergnesB, SerenoD, et al. (2007) SIR2-deficient Leishmania infantum induces a defined IFN-gamma/IL-10 pattern that correlates with protection. J Immunol 179: 3161–3170.

65. Gibson-CorleyKN, BoggiattoPM, BockenstedtMM, PetersenCA, WaldschmidtTJ, et al. (2012) Promotion of a functional B cell germinal center response after Leishmania species co-infection is associated with lesion resolution. Am J Pathol 180: 2009–2017.

66. SilvestreR, SantaremN, CunhaJ, CardosoL, NietoJ, et al. (2008) Serological evaluation of experimentally infected dogs by LicTXNPx-ELISA and amastigote-flow cytometry. Vet Parasitol 158: 23–30.

67. LaforgeM, Campillo-GimenezL, MonceauxV, CumontMC, HurtrelB, et al. (2011) HIV/SIV infection primes monocytes and dendritic cells for apoptosis. PLoS Pathog 7: e1002087.

68. PreibischS, SaalfeldS, TomancakP (2009) Globally optimal stitching of tiled 3D microscopic image acquisitions. Bioinformatics 25: 1463–1465.