ICOS-deficient and ICOS YF mutant mice fail to control Toxoplasma gondii infection of the brain


Autoři: Carleigh A. O’Brien aff001;  Tajie H. Harris aff001
Působiště autorů: Center for Brain Immunology and Glia, Department of Neuroscience, University of Virginia, Charlottesville, VA, United States of America aff001
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
doi: 10.1371/journal.pone.0228251

Souhrn

Resistance to chronic Toxoplasma gondii infection requires ongoing recruitment of T cells to the brain. Thus, the factors that promote, sustain, and regulate the T cell response to the parasite in the brain are of great interest. The costimulatory molecule ICOS (inducible T cell costimulator) has been reported to act largely through the PI3K pathway in T cells, and can play pro-inflammatory or pro-regulatory roles depending on the inflammatory context and T cell type being studied. During infection with T. gondii, ICOS promotes early T cell responses, while in the chronic stage of infection ICOS plays a regulatory role by limiting T cell responses in the brain. We sought to characterize the role of ICOS signaling through PI3K during chronic infection using two models of ICOS deficiency: total ICOS knockout (KO) mice and ICOS YF mice that are unable to activate PI3K signaling. Overall, ICOS KO and ICOS YF mice had similar severe defects in parasite-specific IgG production and parasite control compared to WT mice. Additionally, we observed expanded effector T cell populations and a loss of Treg frequency in the brains of both ICOS KO and ICOS YF mice. When comparing the remaining Treg populations in infected mice, ICOS KO Tregs expressed WT levels of Foxp3 and CD25, while ICOS YF Tregs expressed significantly less Foxp3 and CD25 compared to both WT and ICOS KO mice. Together, these results suggest that PI3K-independent signaling downstream of ICOS plays an important role in Treg stability in the context of chronic inflammation.

Klíčová slova:

Analysis of variance – Cytotoxic T cells – Inflammation – Parasitic diseases – Regulatory T cells – Spleen – T cells – Toxoplasma gondii


Zdroje

1. O’Brien CA, Overall C, Konradt C, O’Hara Hall AC, Hayes NW, Wagage S, et al. CD11c-Expressing Cells Affect Regulatory T Cell Behavior in the Meninges during Central Nervous System Infection. The Journal of Immunology. 2017. doi: 10.4049/jimmunol.1601581 28389591

2. Landrith TA, Harris TH, Wilson EH, editors. Characteristics and critical function of CD8+ T cells in the Toxoplasma-infected brain. Seminars in immunopathology; 2015: Springer.

3. John B, Harris TH, Tait ED, Wilson EH, Gregg B, Ng LG, et al. Dynamic imaging of CD8+ T cells and dendritic cells during infection with Toxoplasma gondii. PLoS pathogens. 2009;5(7):e1000505. doi: 10.1371/journal.ppat.1000505 19578440

4. Ricardo Gazzinelli YX, Sara Hieny, Allen Cheever, Alan Sher. Simultaneous depletion of CD4+ and CD8+ T lymphocytes is required to reactivate chronic infection with Toxoplasma gondii. Journal of immunology. 1992;149(1):175–80.

5. Wilson EH, Wille-Reece U, Dzierszinski F, Hunter CA. A critical role for IL-10 in limiting inflammation during toxoplasmic encephalitis. Journal of neuroimmunology. 2005;165(1):63–74.

6. Stumhofer JS, Laurence A, Wilson EH, Huang E, Tato CM, Johnson LM, et al. Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system. Nat Immunol. 2006;7(9):937–45. doi: 10.1038/ni1376 16906166.

7. O'Brien CA, Batista SJ, Still KM, Harris TH. IL-10 and ICOS Differentially Regulate T Cell Responses in the Brain during Chronic Toxoplasma gondii Infection. Journal of immunology. 2019;202(6):1755–66. doi: 10.4049/jimmunol.1801229 30718297; PubMed Central PMCID: PMC6401250.

8. Oldenhove G, Bouladoux N, Wohlfert EA, Hall JA, Chou D, O'Brien S, et al. Decrease of Foxp3+ Treg cell number and acquisition of effector cell phenotype during lethal infection. Immunity. 2009;31(5):772–86. doi: 10.1016/j.immuni.2009.10.001 19896394

9. Harris T. KC, O'Hara Hall AC., O'Brien C., Hayes NW., Wagage S., John B., Christian DA., Bouladoux N., Belkaid Y., Hunter CA. Tregs form LFA-1-dependent contacts with DCs during CNS infection. Journal of Immunology (Submitted). 2015.

10. Carreno BM, Collins M. The B7 family of ligands and its receptors: new pathways for costimulation and inhibition of immune responses. Annual review of immunology. 2002;20:29–53. doi: 10.1146/annurev.immunol.20.091101.091806 11861596.

11. Yoshinaga SK, Whoriskey JS, Khare SD, Sarmiento U, Guo J, Horan T, et al. T-cell co-stimulation through B7RP-1 and ICOS. Nature. 1999;402(6763):827–32. doi: 10.1038/45582 10617205.

12. Rudd CE, Schneider H. Unifying concepts in CD28, ICOS and CTLA4 co-receptor signalling. Nature reviews Immunology. 2003;3(7):544–56. doi: 10.1038/nri1131 12876557.

13. Wikenheiser DJ, Stumhofer JS. ICOS Co-Stimulation: Friend or Foe? Frontiers in Immunology. 2016;7(304). doi: 10.3389/fimmu.2016.00304 27559335

14. Mak TW, Shahinian A, Yoshinaga SK, Wakeham A, Boucher LM, Pintilie M, et al. Costimulation through the inducible costimulator ligand is essential for both T helper and B cell functions in T cell-dependent B cell responses. Nat Immunol. 2003;4(8):765–72. doi: 10.1038/ni947 12833154.

15. Bauquet AT, Jin H, Paterson AM, Mitsdoerffer M, Ho IC, Sharpe AH, et al. 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. 2009;10(2):167–75. doi: 10.1038/ni.1690 19098919; PubMed Central PMCID: PMC2742982.

16. Warnatz K, Bossaller L, Salzer U, Skrabl-Baumgartner A, Schwinger W, van der Burg M, et al. Human ICOS deficiency abrogates the germinal center reaction and provides a monogenic model for common variable immunodeficiency. Blood. 2006;107(8):3045–52. doi: 10.1182/blood-2005-07-2955 16384931.

17. McAdam AJ, Greenwald RJ, Levin MA, Chernova T, Malenkovich N, Ling V, et al. ICOS is critical for CD40-mediated antibody class switching. Nature. 2001;409(6816):102–5. doi: 10.1038/35051107 11343122.

18. Wilson EH, Zaph C, Mohrs M, Welcher A, Siu J, Artis D, et al. B7RP-1-ICOS Interactions Are Required for Optimal Infection-Induced Expansion of CD4+ Th1 and Th2 Responses. The Journal of Immunology. 2006;177(4):2365–72. doi: 10.4049/jimmunol.177.4.2365 16887998

19. Tafuri A, Shahinian A, Bladt F, Yoshinaga SK, Jordana M, Wakeham A, et al. ICOS is essential for effective T-helper-cell responses. Nature. 2001;409(6816):105–9. doi: 10.1038/35051113 11343123.

20. Nouailles G, Day TA, Kuhlmann S, Loewe D, Dorhoi A, Gamradt P, et al. Impact of inducible co-stimulatory molecule (ICOS) on T-cell responses and protection against Mycobacterium tuberculosis infection. Eur J Immunol. 2011;41(4):981–91. doi: 10.1002/eji.201040608 21337542.

21. Mittrucker HW, Kursar M, Kohler A, Yanagihara D, Yoshinaga SK, Kaufmann SH. Inducible costimulator protein controls the protective T cell response against Listeria monocytogenes. Journal of immunology. 2002;169(10):5813–7. doi: 10.4049/jimmunol.169.10.5813 12421962.

22. Simpson TR, Quezada SA, Allison JP. Regulation of CD4 T cell activation and effector function by inducible costimulator (ICOS). Curr Opin Immunol. 2010;22(3):326–32. doi: 10.1016/j.coi.2010.01.001 20116985.

23. Akbari O, Freeman GJ, Meyer EH, Greenfield EA, Chang TT, Sharpe AH, et al. Antigen-specific regulatory T cells develop via the ICOS-ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity. Nat Med. 2002;8(9):1024–32. doi: 10.1038/nm745 12145647.

24. Herman AE, Freeman GJ, Mathis D, Benoist C. CD4+CD25+ T regulatory cells dependent on ICOS promote regulation of effector cells in the prediabetic lesion. J Exp Med. 2004;199(11):1479–89. doi: 10.1084/jem.20040179 15184501; PubMed Central PMCID: PMC2211778.

25. Redpath SA, van der Werf N, Cervera AM, MacDonald AS, Gray D, Maizels RM, et al. ICOS controls Foxp3(+) regulatory T-cell expansion, maintenance and IL-10 production during helminth infection. Eur J Immunol. 2013;43(3):705–15. doi: 10.1002/eji.201242794 23319295; PubMed Central PMCID: PMC3615169.

26. Villegas-Mendez A, Shaw TN, Inkson CA, Strangward P, de Souza JB, Couper KN. Parasite-Specific CD4+ IFN-γ+ IL-10+ T Cells Distribute within Both Lymphoid and Nonlymphoid Compartments and Are Controlled Systemically by Interleukin-27 and ICOS during Blood-Stage Malaria Infection. Infection and immunity. 2016;84(1):34–46. doi: 10.1128/IAI.01100-15 26459508

27. Smigiel KS, Richards E, Srivastava S, Thomas KR, Dudda JC, Klonowski KD, et al. CCR7 provides localized access to IL-2 and defines homeostatically distinct regulatory T cell subsets. The Journal of experimental medicine. 2014;211(1):121–36. doi: 10.1084/jem.20131142 24378538

28. Villegas EN, Lieberman LA, Mason N, Blass SL, Zediak VP, Peach R, et al. A role for inducible costimulator protein in the CD28- independent mechanism of resistance to Toxoplasma gondii. Journal of immunology. 2002;169(2):937–43. doi: 10.4049/jimmunol.169.2.937 12097399.

29. Gigoux M, Shang J, Pak Y, Xu M, Choe J, Mak TW, et al. Inducible costimulator promotes helper T-cell differentiation through phosphoinositide 3-kinase. Proceedings of the National Academy of Sciences of the United States of America. 2009;106(48):20371–6. doi: 10.1073/pnas.0911573106 19915142; PubMed Central PMCID: PMC2787139.

30. Chen Dong AEJ, Ulla-Angela Temann, Sujan Shresta, Allison James P, Ruddle Nancy H., Flavell Richard A. ICOS co-stimulatory receptor is essential for T-cell activation and function. Nature. 2001;409:97–101. doi: 10.1038/35051100 11343121

31. Glatman Zaretsky A, Silver JS, Siwicki M, Durham A, Ware CF, Hunter CA. Infection with Toxoplasma gondii alters lymphotoxin expression associated with changes in splenic architecture. Infect Immun. 2012;80(10):3602–10. doi: 10.1128/IAI.00333-12 22851754; PubMed Central PMCID: PMC3457551.

32. Wikenheiser DJ, Ghosh D, Kennedy B, Stumhofer JS. The costimulatory molecule ICOS regulates host Th1 and follicular Th cell differentiation in response to Plasmodium chabaudi chabaudi AS infection. The Journal of Immunology. 2016;196(2):778–91. doi: 10.4049/jimmunol.1403206 26667167

33. Choi YS, Kageyama R, Eto D, Escobar TC, Johnston RJ, Monticelli L, et al. ICOS receptor instructs T follicular helper cell versus effector cell differentiation via induction of the transcriptional repressor Bcl6. Immunity. 2011;34(6):932–46. doi: 10.1016/j.immuni.2011.03.023 21636296; PubMed Central PMCID: PMC3124577.

34. Akiba H, Takeda K, Kojima Y, Usui Y, Harada N, Yamazaki T, et al. The role of ICOS in the CXCR5+ follicular B helper T cell maintenance in vivo. Journal of immunology. 2005;175(4):2340–8. doi: 10.4049/jimmunol.175.4.2340 16081804.

35. Fos C, Salles A, Lang V, Carrette F, Audebert S, Pastor S, et al. ICOS ligation recruits the p50α PI3K regulatory subunit to the immunological synapse. The Journal of Immunology. 2008;181(3):1969–77. doi: 10.4049/jimmunol.181.3.1969 18641334

36. Wu Y, Borde M, Heissmeyer V, Feuerer M, Lapan AD, Stroud JC, et al. FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell. 2006;126(2):375–87. doi: 10.1016/j.cell.2006.05.042 16873067.

37. Chen C, Rowell EA, Thomas RM, Hancock WW, Wells AD. Transcriptional regulation by Foxp3 is associated with direct promoter occupancy and modulation of histone acetylation. The Journal of biological chemistry. 2006;281(48):36828–34. doi: 10.1074/jbc.M608848200 17028180.

38. Clark LB, Appleby MW, Brunkow ME, Wilkinson JE, Ziegler SF, Ramsdell F. Cellular and molecular characterization of the scurfy mouse mutant. Journal of immunology. 1999;162(5):2546–54. 10072494.

39. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol. 2003;4(4):330–6. doi: 10.1038/ni904 12612578.

40. Chinen T, Kannan AK, Levine AG, Fan X, Klein U, Zheng Y, et al. An essential role for the IL-2 receptor in Treg cell function. Nat Immunol. 2016;17(11):1322–33. doi: 10.1038/ni.3540 27595233; PubMed Central PMCID: PMC5071159.

41. Setoguchi R, Hori S, Takahashi T, Sakaguchi S. Homeostatic maintenance of natural Foxp3(+) CD25(+) CD4(+) regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. J Exp Med. 2005;201(5):723–35. doi: 10.1084/jem.20041982 15753206; PubMed Central PMCID: PMC2212841.

42. Coyle AJ, Lehar S, Lloyd C, Tian J, Delaney T, Manning S, et al. The CD28-related molecule ICOS is required for effective T cell–dependent immune responses. Immunity. 2000;13(1):95–105. doi: 10.1016/s1074-7613(00)00011-x 10933398

43. Bossaller L, Burger J, Draeger R, Grimbacher B, Knoth R, Plebani A, et al. ICOS deficiency is associated with a severe reduction of CXCR5+ CD4 germinal center Th cells. The Journal of Immunology. 2006;177(7):4927–32. doi: 10.4049/jimmunol.177.7.4927 16982935

44. Kang H, Remington JS, Suzuki Y. Decreased resistance of B cell-deficient mice to infection with Toxoplasma gondii despite unimpaired expression of IFN-gamma, TNF-alpha, and inducible nitric oxide synthase. Journal of immunology. 2000;164(5):2629–34. doi: 10.4049/jimmunol.164.5.2629 10679102.

45. Hill DE, Chirukandoth S, Dubey J. Biology and epidemiology of Toxoplasma gondii in man and animals. Animal Health Research Reviews. 2005;6(01):41–61.

46. Saeij JP, Boyle JP, Grigg ME, Arrizabalaga G, Boothroyd JC. Bioluminescence imaging of Toxoplasma gondii infection in living mice reveals dramatic differences between strains. Infect Immun. 2005;73(2):695–702. doi: 10.1128/IAI.73.2.695-702.2005 15664907; PubMed Central PMCID: PMC547072.

47. Tenter AM, Heckeroth AR, Weiss LM. Toxoplasma gondii: from animals to humans. International journal for parasitology. 2000;30(12):1217–58.

48. Filisetti D, Candolfi E. Immune response to Toxoplasma gondii. Ann Ist Super Sanita. 2004;40(1):71–80. 15269455

49. Suzuki Y, Orellana M, Schreiber R, Remington J. Interferon-gamma: the major mediator of resistance against Toxoplasma gondii. Science. 1988;240(4851):516–8. doi: 10.1126/science.3128869 3128869

50. Riley JL, Mao M, Kobayashi S, Biery M, Burchard J, Cavet G, et al. Modulation of TCR-induced transcriptional profiles by ligation of CD28, ICOS, and CTLA-4 receptors. Proceedings of the National Academy of Sciences of the United States of America. 2002;99(18):11790–5. doi: 10.1073/pnas.162359999 12195015; PubMed Central PMCID: PMC129347.

51. Li J, Heinrichs J, Leconte J, Haarberg K, Semple K, Liu C, et al. Phosphatidylinositol 3-kinase-independent signaling pathways contribute to ICOS-mediated T cell costimulation in acute graft-versus-host disease in mice. Journal of immunology. 2013;191(1):200–7. doi: 10.4049/jimmunol.1203485 23729441; PubMed Central PMCID: PMC4318500.

52. Pedros C, Zhang Y, Hu JK, Choi YS, Canonigo-Balancio AJ, Yates JR 3rd, et al. A TRAF-like motif of the inducible costimulator ICOS controls development of germinal center TFH cells via the kinase TBK1. Nat Immunol. 2016;17(7):825–33. doi: 10.1038/ni.3463 27135603; PubMed Central PMCID: PMC4915981.

53. Abu-Eid R, Samara RN, Ozbun L, Abdalla MY, Berzofsky JA, Friedman KM, et al. Selective inhibition of regulatory T cells by targeting the PI3K-Akt pathway. Cancer Immunol Res. 2014;2(11):1080–9. doi: 10.1158/2326-6066.CIR-14-0095 25080445; PubMed Central PMCID: PMC4221428.

54. Sauer S, Bruno L, Hertweck A, Finlay D, Leleu M, Spivakov M, et al. T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(22):7797–802. doi: 10.1073/pnas.0800928105 18509048; PubMed Central PMCID: PMC2409380.

55. Grimbacher B, Hutloff A, Schlesier M, Glocker E, Warnatz K, Drager R, et al. Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency. Nat Immunol. 2003;4(3):261–8. doi: 10.1038/ni902 12577056.

56. Roussel L, Landekic M, Golizeh M, Gavino C, Zhong MC, Chen J, et al. Loss of human ICOSL results in combined immunodeficiency. J Exp Med. 2018;215(12):3151–64. doi: 10.1084/jem.20180668 30498080; PubMed Central PMCID: PMC6279397.

57. Cunningham-Rundles C, Bodian C. Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol. 1999;92(1):34–48. doi: 10.1006/clim.1999.4725 10413651.

58. Yong PF, Salzer U, Grimbacher B. The role of costimulation in antibody deficiencies: ICOS and common variable immunodeficiency. Immunol Rev. 2009;229(1):101–13. doi: 10.1111/j.1600-065X.2009.00764.x 19426217.

59. Cunningham-Rundles C. Autoimmune manifestations in common variable immunodeficiency. J Clin Immunol. 2008;28 Suppl 1:S42–5. doi: 10.1007/s10875-008-9182-7 18322785; PubMed Central PMCID: PMC2694614.

60. Azizi G, Hafezi N, Mohammadi H, Yazdani R, Alinia T, Tavakol M, et al. Abnormality of regulatory T cells in common variable immunodeficiency. Cell Immunol. 2017;315:11–7. doi: 10.1016/j.cellimm.2016.12.007 28284485.

61. Varzaneh FN, Keller B, Unger S, Aghamohammadi A, Warnatz K, Rezaei N. Cytokines in common variable immunodeficiency as signs of immune dysregulation and potential therapeutic targets—a review of the current knowledge. J Clin Immunol. 2014;34(5):524–43. doi: 10.1007/s10875-014-0053-0 24827633.

62. Arandi N, Mirshafiey A, Abolhassani H, Jeddi-Tehrani M, Edalat R, Sadeghi B, et al. Frequency and expression of inhibitory markers of CD4(+) CD25(+) FOXP3(+) regulatory T cells in patients with common variable immunodeficiency. Scand J Immunol. 2013;77(5):405–12. doi: 10.1111/sji.12040 23432692.

63. Oliva A, Scala E, Quinti I, Paganelli R, Ansotegui IJ, Giovannetti A, et al. IL-10 production and CD40L expression in patients with common variable immunodeficiency. Scand J Immunol. 1997;46(1):86–90. doi: 10.1046/j.1365-3083.1997.d01-95.x 9246212.

64. Fevang B, Yndestad A, Sandberg WJ, Holm AM, Muller F, Aukrust P, et al. Low numbers of regulatory T cells in common variable immunodeficiency: association with chronic inflammation in vivo. Clin Exp Immunol. 2007;147(3):521–5. doi: 10.1111/j.1365-2249.2006.03314.x 17302902; PubMed Central PMCID: PMC1810487.

65. Genre J, Errante PR, Kokron CM, Toledo-Barros M, Camara NO, Rizzo LV. Reduced frequency of CD4(+)CD25(HIGH)FOXP3(+) cells and diminished FOXP3 expression in patients with Common Variable Immunodeficiency: a link to autoimmunity? Clin Immunol. 2009;132(2):215–21. doi: 10.1016/j.clim.2009.03.519 19394278.

66. Wong GK, Huissoon AP. T-cell abnormalities in common variable immunodeficiency: the hidden defect. Journal of clinical pathology. 2016;69(8):672–6. doi: 10.1136/jclinpath-2015-203351 27153873

67. Giovannetti A, Pierdominici M, Mazzetta F, Marziali M, Renzi C, Mileo AM, et al. Unravelling the complexity of T cell abnormalities in common variable immunodeficiency. The Journal of Immunology. 2007;178(6):3932–43. doi: 10.4049/jimmunol.178.6.3932 17339494


Článek vyšel v časopise

PLOS One


2020 Číslo 1