Disruption of IL-21 Signaling Affects T Cell-B Cell Interactions and Abrogates Protective Humoral Immunity to Malaria

English version České info

The importance of antibody and B-cell responses for control of the erythrocytic-stage of the malaria parasite, Plasmodium, was first described when immune serum, passively transferred into Plasmodium falciparum-infected children, reduced parasitemia. This was later confirmed in experimental models in which mice deficient in B cells were unable to eliminate erythrocytic-stage infections. The signals required to activate these protective long-lasting B cell responses towards Plasmodium have not been investigated. IL-21 has been shown to be important for development of B-cell responses after immunization; however, a direct requirement for IL-21 in the control of infection via B-cell dependent mechanisms has never been demonstrated. In this paper, we have used mouse models of erythrocytic P. chabaudi and P. yoelii 17X(NL) infections in combination with IL-21/IL-21R deficiency to show that IL-21 from CD4+ T cells is required to eliminate Plasmodium infection by activating protective, long-lasting B-cell responses. Disruption of IL-21 signaling in B cells prevents the elimination of the parasite resulting in sustained high parasitemias, with no development of memory B-cells, lack of antigen-specific plasma cells and antibodies, and thus no protective immunity against a second challenge infection. Our data demonstrate the absolute requirement of IL-21 for B-cell control of this systemic infection. This has important implications for the design of vaccines against Plasmodium.

Vyšlo v časopise: Disruption of IL-21 Signaling Affects T Cell-B Cell Interactions and Abrogates Protective Humoral Immunity to Malaria. PLoS Pathog 11(3): e32767. doi:10.1371/journal.ppat.1004715
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004715

Souhrn

Zdroje

1. World Health Organization. (2013) World Malaria Report. 2013 : 1–286.

2. Cohen S, McGregor IA, and Carrington S. (1961) Gamma-globulin and acquired immunity to human malaria. Nature. 192 : 733–7. 13880318

3. Conway DJ, Cavanagh DR, Tanabe K, Roper C, Mikes ZS, et al. (2000) A principal target of human immunity to malaria identified by molecular population genetic and immunological analyses. Nat Med. 6(6):689–92. 10835687

4. Fowkes FJI, Richards JS, Simpson JA, and Beeson JG. (2010) The relationship between anti-merozoite antibodies and incidence of Plasmodium falciparum malaria: A systematic review and meta-analysis. PLoS Med. 7(1):e1000218. doi: 10.1371/journal.pmed.1000218 20098724

5. Osier FHA, Fegan G, Polley SD, Murungi L, Verra F, et al. (2008) Breadth and magnitude of antibody responses to multiple Plasmodium falciparum merozoite antigens are associated with protection from clinical malaria. Infect Immun. 76(5):2240–8. doi: 10.1128/IAI.01585-07 18316390

6. Sabchareon A, Burnouf T, Ouattara D, Attanath P, Bouharoun-Tayoun H, et al. (1991) Parasitologic and clinical human response to immunoglobulin administration in falciparum malaria. Am J Trop Med Hyg. 45(3):297–308. 1928564

7. Burns JM Jr., Dunn PD, and Russo DM. (1997) Protective immunity against Plasmodium yoelii malaria induced by immunization with particulate blood-stage antigens. Infect Immun. 65(8):3138–45. 9234766

8. von der Weid T, Honarvar N, and Langhorne J. (1996) Gene-targeted mice lacking B cells are unable to eliminate a blood stage malaria infection. J Immunol. 156(7):2510–6. 8786312

9. Crotty S. (2011) Follicular helper CD4 T cells (TFH). Annu Rev Immunol. 29 : 621–63. doi: 10.1146/annurev-immunol-031210-101400 21314428

10. Linterman MA, and Vinuesa CG. (2010) T follicular helper cells during immunity and tolerance. Prog Mol Biol Transl Sci. 92 : 207–48. doi: 10.1016/S1877-1173(10)92009-7 20800823

11. Bessa J, Kopf M, and Bachmann MF. (2010) Cutting edge: IL-21 and TLR signaling regulate germinal center responses in a B cell-intrinsic manner. J Immunol. 184(9):4615–9. doi: 10.4049/jimmunol.0903949 20368279

12. Dorfmeier CL, Tzvetkov EP, Gatt A, and McGettigan JP. (2013) Investigating the Role for IL-21 in Rabies Virus Vaccine-induced Immunity. PLoS Neg Trop Dis. 7(3):e2129. doi: 10.1371/journal.pntd.0002129 23516660

13. Eto D, Lao C, DiToro D, Barnett B, Escobar TC, et al. (2011) IL-21 and IL-6 are critical for different aspects of B cell immunity and redundantly induce optimal follicular helper CD4 T cell (Tfh) differentiation. PloS One. 6(3):e17739. doi: 10.1371/journal.pone.0017739 21423809

14. King IL, Mohrs K, and Mohrs M. (2010) A nonredundant role for IL-21 receptor signaling in plasma cell differentiation and protective type 2 immunity against gastrointestinal helminth infection. J Immunol. 185(10):6138–45. doi: 10.4049/jimmunol.1001703 20926797

15. Linterman MA, Beaton L, Yu D, Ramiscal RR, Srivastava M, et al. (2010) IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses. J Exp Med. 207(2):353–63. doi: 10.1084/jem.20091738 20142429

16. Nurieva RI, Chung Y, Hwang D, Yang XO, Kang HS, 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(1):138–49. doi: 10.1016/j.immuni.2008.05.009 18599325

17. Phares TW, DiSano KD, Hinton DR, Hwang M, Zajac AJ, et al. (2013) IL-21 optimizes T cell and humoral responses in the central nervous system during viral encephalitis. J Neuroimmunol. 263(1–2):43–54. doi: 10.1016/j.jneuroim.2013.08.007 24035008

18. Rankin AL, MacLeod H, Keegan S, Andreyeva T, Lowe L, et al. (2011) IL-21 receptor is critical for the development of memory B cell responses. J Immunol. 186(2):667–74. doi: 10.4049/jimmunol.0903207 21169545

19. Rasheed MAU, Latner DR, Aubert RD, Gourley T, Spolski R, et al. (2013) Interleukin-21 is a critical cytokine for the generation of virus-specific long-lived plasma cells. J Virol. 87(13):7737–46. doi: 10.1128/JVI.00063-13 23637417

20. Stumhofer JS, Silver JS, and Hunter CA. (2013) IL-21 Is Required for Optimal Antibody Production and T Cell Responses during Chronic Toxoplasma gondii Infection. PloS One. 8(5):e62889. doi: 10.1371/journal.pone.0062889 23667536

21. Vogelzang A, McGuire HM, Yu D, Sprent J, Mackay CR, et al. (2008) A fundamental role for interleukin-21 in the generation of T follicular helper cells. Immunity. 29(1):127–37. doi: 10.1016/j.immuni.2008.06.001 18602282

22. Yi JS, Du M, and Zajac AJ. (2009) A Vital Role for Interleukin-21 in the Control of a Chronic Viral Infection. Science. 324(5934):1572–6. doi: 10.1126/science.1175194 19443735

23. Zotos D, Coquet JM, Zhang Y, Light A, D'Costa K, et al. (2010) IL-21 regulates germinal center B cell differentiation and proliferation through a B cell-intrinsic mechanism. J Exp Med. 207(2):365–78. doi: 10.1084/jem.20091777 20142430

24. Ozaki K, Spolski R, Feng C, Qi C, Cheng J, Sher A, et al. (2002) A Critical Role for IL-21 in Regulating Immunoglobulin Production. Science. 298(5598):1630–4. 12446913

25. Elsaesser H, Sauer K, and Brooks DG. (2009) IL-21 is required to control chronic viral infection. Science. 324(5934):1569–72. doi: 10.1126/science.1174182 19423777

26. Fröhlich A, Kisielow J, Schmitz I, Freigang S, Shamshiev AT, et al. (2009) IL-21R on T cells is critical for sustained functionality and control of chronic viral infection. Science. 324(5934):1576–80. doi: 10.1126/science.1172815 19478140

27. Achtman AH, Stephens R, Cadman ET, Harrison V, and Langhorne J. (2007) Malaria-specific antibody responses and parasite persistence after infection of mice with Plasmodium chabaudi chabaudi. Parasite Immunol. 29(9):435–44. 17727567

28. Philpott KL, Viney JL, Kay G, Rastan S, Gardiner EM, et al. (1992) Lymphoid development in mice congenitally lacking T cell receptor alpha beta-expressing cells. Science. 256(5062):1448–52. 1604321

29. Kitamura D, Roes J, Kühn R, and Rajewsky K. (1991) A B cell-deficient mouse by targeted disruption of the membrane exon of the immunoglobulin μ chain gene. Nature. 350(6317):423–6. 1901381

30. Linterman MA, Pierson W, Lee SK, Kallies A, Kawamoto S, et al. (2011) Foxp3+ follicular regulatory T cells control the germinal center response. Nat Med. 17(8):975–82. doi: 10.1038/nm.2425 21785433

31. Cannons JL, Qi H, Lu KT, Dutta M, Gomez-Rodriguez J, 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(2):253–65. doi: 10.1016/j.immuni.2010.01.010 20153220

32. Smith KG, Hewitson TD, Nossal GJ, Tarlinton DM. (1996) The phenotype and fate of the antibody-forming cells of the splenic foci. Eur. J. Immunol. 26 : 444–48. 8617316

33. Karnowski A, Chevrier S, Belz GT, Mount A, Emslie D, et al. (2012) B and T cells collaborate in antiviral responses via IL-6, IL-21, and transcriptional activator and coactivator, Oct2 and OBF-1. J Exp Med. 209(11):2049–64. doi: 10.1084/jem.20111504 23045607

34. Nurieva RI, Chung Y, Martinez GJ, Yang XO, Tanaka S, et al. (2009) Bcl6 mediates the development of T follicular helper cells. Science. 325(5943):1001–5. doi: 10.1126/science.1176676 19628815

35. Barker BR, Gladstone MN, Gillard GO, Panas MW, and Letvin NL. (2010) Critical role for IL-21 in both primary and memory anti-viral CD8+ T-cell responses. Eur J Immunol. 40(11):3085–96. doi: 10.1002/eji.200939939 21061439

36. Li L, Liu M, Cheng L-W, Gao X-Y, Fu J-J, et al. (2013) HBcAg-specific IL-21-producing CD4+ T cells are associated with relative viral control in patients with chronic hepatitis B. Scand J Immunol. 78(5):439–46. doi: 10.1111/sji.12099 23957859

37. Williams LD, Bansal A, Sabbaj S, Heath SL, Song W, et al. (2011) Interleukin-21-producing HIV-1-specific CD8 T cells are preferentially seen in elite controllers. J Virol. 85(5):2316–24. doi: 10.1128/JVI.01476-10 21159862

38. Horne-Debets JM, Faleiro R, Karunarathne DS, Liu XQ, Lineburg KE, et al. (2013) PD-1 Dependent Exhaustion of CD8+ T Cells Drives Chronic Malaria. Cell Rep. 5(5):1204–13. doi: 10.1016/j.celrep.2013.11.002 24316071

39. Imai T, Shen J, Chou B, Duan X, Tu L, et al. (2010) Involvement of CD8+ T cells in protective immunity against murine blood-stage infection with Plasmodium yoelii 17XL strain. Eur J Immunol. 40(4):1053–61. doi: 10.1002/eji.200939525 20101613

40. Mogil RJ, Patton CL, and Green DR. (1987) Cellular subsets involved in cell-mediated immunity to murine Plasmodium yoelii 17X malaria. J Immunol. 138(6):1933–9. 3102605

41. Podoba JE, and Stevenson MM. (1991) CD4+ and CD8+ T lymphocytes both contribute to acquired immunity to blood-stage Plasmodium chabaudi AS. Infect Immun. 59(1):51–8. 1898902

42. Süss G, Eichmann K, Kury E, Linke A, and Langhorne J. (1988) Roles of CD4 -⁠ and CD8-bearing T lymphocytes in the immune response to the erythrocytic stages of Plasmodium chabaudi. Infect Immun. 56(12):3081–8. 2903123

43. Carter R, and Walliker D. (1975) New observations on the malaria parasites of rodents of the Central African Republic—Plasmodium vinckei petteri subsp. nov. and Plasmodium chabaudi Landau, 1965. Ann Trop Med Parasitol. 69(2):187–96. 1155987

44. Yi JS, Cox MA, Zajac AJ. (2010) Interleukin-21: a multifunctional regulator of immunity to infections. Microbes Infect. 12(14–15):1111–9. doi: 10.1016/j.micinf.2010.07.015 20691803

45. Liehl P, Mota MM. (2012) Innate recognition of malarial parasites by mammalian hosts. Int J Parasitol. 42 (6):557–6. doi: 10.1016/j.ijpara.2012.04.006 22543040

46. Cannons JL, Lu KT, and Schwartzberg PL. (2013) T follicular helper cell diversity and plasticity. Trends Immunol. 34(5):200–7. doi: 10.1016/j.it.2013.01.001 23395212

47. Nakayamada S, Takahashi H, Kanno Y, and O'Shea JJ. (2012) Helper T cell diversity and plasticity. Curr Opin Immunol. 24(3):297–302. doi: 10.1016/j.coi.2012.01.014 22341735

48. Mastelic B, do Rosario APF, Veldhoen M, Renauld JC, Jarra W, et al. (2012) IL-22 Protects Against Liver Pathology and Lethality of an Experimental Blood-Stage Malaria Infection. Front Immunol. 25;3 : 85.

49. Freitas do Rosário AP, Lamb T, Spence P, Stephens R, Lang A, et al. (2012) IL-27 promotes IL-10 production by effector Th1 CD4+ T cells: a critical mechanism for protection from severe immunopathology during malaria infection. J Immunol. 188(3):1178–90. doi: 10.4049/jimmunol.1102755 22205023

50. Li C, Corraliza I, and Langhorne J. (1999) Defect in Interleukin-10 Leads to Enhanced Malarial Disease in Plasmodium chabaudi chabaudi Infection in Mice. Infect Immun. 4435–42. 10456884

51. Mewono L, Agnandji ST, Matondo Maya DW, Mouima A-MN, Iroungou BA, et al. (2009) Malaria antigen-mediated enhancement of interleukin-21 responses of peripheral blood mononuclear cells in African adults. Exp Parasitol. 122(1):37–40. doi: 10.1016/j.exppara.2009.01.007 19545527

52. Roetynck S, Olotu A, Simam J, Marsh K, Stockinger B, et al. (2013) Phenotypic and functional profiling of CD4 T cell compartment in distinct populations of healthy adults with different antigenic exposure. PloS One. 8(1):e55195. doi: 10.1371/journal.pone.0055195 23383106

53. Mewono L, Matondo Maya DW, Matsiegui P-B, Agnandji ST, Kendjo E, et al. (2008) Interleukin-21 is associated with IgG1 and IgG3 antibodies to erythrocyte-binding antigen-175 peptide 4 of Plasmodium falciparum in Gabonese children with acute falciparum malaria. Eur Cytokine Netw. 19(1):30–6. doi: 10.1684/ecn.2008.0114 18299268

54. Shinkai Y, Rathbun G, Lam KP, Oltz EM, Stewart V, et al. (1992) RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell. 68(5):855–67. 1547487

55. Fröhlich A, Marsland BJ, Sonderegger I, Kurrer M, Hodge MR, et al. (2007) IL-21 receptor signaling is integral to the development of Th2 effector responses in vivo. Blood. 109(5):2023–31. 17077330

56. Cadman ET, Abdallah AY, Voisine C, Sponaas A-M, Corran P, et al. (2008) Alterations of splenic architecture in malaria are induced independently of Toll-like receptors 2, 4, and 9 or MyD88 and may affect antibody affinity. Infect Immun. 76(9):3924–31. doi: 10.1128/IAI.00372-08 18559428

57. Unkeless JC. (1979) Characterization of a monoclonal antibody directed against mouse macrophage and lymphocyte Fc receptors. J Exp Med. 150(3):580–96. 90108

58. Hiramatsu Y, Suto A, Kashiwakuma D, Kanari H, Kagami S-i, et al. (2010) c-Maf activates the promoter and enhancer of the IL-21 gene, and TGF-beta inhibits c-Maf-induced IL-21 production in CD4+ T cells. J Leukoc Biol. 87(4):703–12. doi: 10.1189/jlb.0909639 20042469

59. Kashiwakuma D, Suto A, Hiramatsu Y, Ikeda K, Takatori H, et al. (2010) B and T lymphocyte attenuator suppresses IL-21 production from follicular Th cells and subsequent humoral immune responses. J Immunol. 185(5):2730–6. doi: 10.4049/jimmunol.0903839 20660710

60. Nakayamada S, Kanno Y, Takahashi H, Jankovic D, Lu KT, et al. (2011) Early Th1 Cell Differentiation Is Marked by a Tfh Cell-like Transition. Immunity. 35(6):919–31. doi: 10.1016/j.immuni.2011.11.012 22195747

61. Ndungu FM, Cadman ET, Coulcher J, Nduati E, Couper E, et al. (2009) Functional Memory B Cells and Long-Lived Plasma Cells Are Generated after a Single Plasmodium chabaudi Infection in Mice. PLoS Pathog. 5(12):e1000690. doi: 10.1371/journal.ppat.1000690 20011127

62. Hensmann M, Li C, Moss C, Lindo V, Greer F, et al. (2004) Disulfide bonds in merozoite surface protein 1 of the malaria parasite impede efficient antigen processing and affect the in vivo antibody response. Eur J Immunol. 34(3):639–48. 14991593

63. Hu Y, and Smyth G. (2009) ELDA: Extreme limiting dilution analysis for comparing depleted and enriched populations in stem cell and other assays. J Immunol Methods. 347(1–2):70–8. doi: 10.1016/j.jim.2009.05.013 19520083

64. Quin SJ, and Langhorne J. (2001) Different regions of the malaria merozoite surface protein 1 of Plasmodium chabaudi elicit distinct T-cell and antibody isotype responses. Infect Immun. 69(4):2245–51. 11254580