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Skewed T cell responses to Epstein-Barr virus in long-term asymptomatic kidney transplant recipients


Autoři: Cecilia Nakid-Cordero aff001;  Nadia Arzouk aff002;  Nicolas Gauthier aff001;  Nadine Tarantino aff001;  Martin Larsen aff001;  Sylvain Choquet aff001;  Sonia Burrel aff001;  Brigitte Autran aff001;  Vincent Vieillard aff001;  Amélie Guihot aff001
Působiště autorů: Sorbonne Université (Univ. Paris 06), INSERM U1135, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Hôpital Pitié-Salpêtrière, Paris, France aff001;  Service de Néphrologie, Urologie et Transplantation Rénale, Hôpital Pitié Salpêtrière, Paris, France aff002;  CNRS ERL8255, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France aff003;  Service d’Hématologie, Hôpital Pitié Salpêtrière, Paris, France aff004;  Service de Virologie, Hôpital Pitié Salpêtrière, Paris, France aff005;  Département d’Immunologie, Assistance Publique-Hôpitaux de Paris (AP-HP), Groupe Hospitalier Pitié-Salpêtrière, Paris, France aff006
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0224211

Souhrn

Kidney transplant recipients (KTRs) abnormally replicate the Epstein Barr Virus (EBV). To better understand how long-term immunosuppression impacts the immune control of this EBV re-emergence, we systematically compared 10 clinically stable KTRs to 30 healthy controls (HCs). The EBV-specific T cell responses were determined in both groups by multiparameter flow cytometry with intra cellular cytokine staining (KTRs n = 10; HCs n = 15) and ELISpot-IFNγ assays (KTRs n = 7; HCs n = 7). The T/B/NK cell counts (KTRs n = 10; HCs n = 30) and the NK/T cell differentiation and activation phenotypes (KTRs n = 10; HCs n = 15/30) were also measured. We show that in KTRs, the Th1 effector CD4+ T cell responses against latent EBV proteins are weak (2/7 responders). Conversely, the frequencies total EBV-specific CD8+T cells are conserved in KTRs (n = 10) and span a wider range of EBNA-3A peptides (5/7responders) than in HCs (5/7responders). Those modifications of the EBV-specific T cell response were associated with a profound CD4+ T cell lymphopenia in KTRs compared to HCs, involving the naïve CD4+ T cell subset, and a persistent activation of highly-differentiated senescent CD8+ T cells. The proportion of total NK / CD8+ T cells expressing PD-1 was also increased in KTRs. Noteworthy, PD-1 expression on CD8+ T cells normalized with time after transplantation. In conclusion, we show modifications of the EBV-specific cellular immunity in long term transplant recipients. This may be the result of both persistent EBV antigenic stimulation and profound immunosuppression induced by anti-rejection treatments. These findings provide new insights into the immunopathology of EBV infection after renal transplantation.

Klíčová slova:

Cytokines – Cytotoxic T cells – Epstein-Barr virus – Flow cytometry – Immune response – NK cells – Renal transplantation – T cells


Zdroje

1. Abbott RJ, Pachnio A, Pedroza-Pacheco I, Leese AM, Begum J, Long HM, et al. Asymptomatic Primary Infection with Epstein-Barr Virus: Observations on Young Adult Cases. J Virol. 2017;91. doi: 10.1128/JVI.00382-17 28835490

2. Dharnidharka VR. Comprehensive review of post–organ transplant hematologic cancers. Am J Transplant. 2018;18: 537–549. doi: 10.1111/ajt.14603 29178667

3. Sprangers B, Nair V, Launay-Vacher V, Riella L V., Jhaveri KD. Risk factors associated with post-kidney transplant malignancies: An article from the Cancer-Kidney International Network. Clin Kidney J. 2018;11: 315–329. doi: 10.1093/ckj/sfx122 29942495

4. Dierickx D, Habermann TM. Post-Transplantation Lymphoproliferative Disorders in Adults. N Engl J Med. 2018;378: 549–562. doi: 10.1056/NEJMra1702693 29414277

5. Hislop AD, Taylor GS, Sauce D, Rickinson AB. Cellular Responses to Viral Infection in Humans: Lessons from Epstein-Barr Virus. Annu Rev Immunol. 2007;25: 587–617. doi: 10.1146/annurev.immunol.25.022106.141553 17378764

6. Münz C. Epstein-Barr virus-specific immune control by innate lymphocytes. Front Immunol. 2017;8: 1–7. doi: 10.3389/fimmu.2017.00001

7. Williams H, McAulay K, Macsween KF, Gallacher NJ, Higgins CD, Harrison N, et al. The immune response to primary EBV infection: A role for natural killer cells. Br J Haematol. 2005;129: 266–274. doi: 10.1111/j.1365-2141.2005.05452.x 15813855

8. Luque Y, Jamme M, Rabant M, Dewolf S, Noël LH, Thervet E, et al. Long-term CD4 lymphopenia is associated with accelerated decline of kidney allograft function. Nephrol Dial Transplant. 2016;31: 487–495. doi: 10.1093/ndt/gfv362 26492923

9. Glowacki F, Al Morabiti M, Lionet A, Labalette M, Provot F, Noel C, et al. Long-Term Kinetics of a T-Lymphocytes Subset in Kidney Transplant Recipients: Relationship With Posttransplant Malignancies. Transplant Proc. Elsevier Inc.; 2009;41: 3323–3325. doi: 10.1016/j.transproceed.2009.09.033 19857742

10. Mancebo E, Castro MJ, Allende LM, Talayero P, Brunet M, Millán O, et al. High proportion of CD95+and CD38+in cultured CD8+T cells predicts acute rejection and infection, respectively, in kidney recipients. Transpl Immunol. Elsevier B.V.; 2016;34: 33–41. doi: 10.1016/j.trim.2016.01.001 26773856

11. Sester U, Presser D, Dirks J, Gärtner BC, Köhler H, Sester M. PD-1 expression and IL-2 loss of cytomegalovirus- specific t cells correlates with viremia and reversible functional anergy. Am J Transplant. 2008;8: 1486–1497. doi: 10.1111/j.1600-6143.2008.02279.x 18510628

12. La Rosa C, Krishnan A, Longmate J, Martinez J, Manchanda P, Lacey SF, et al. Programmed Death–1 Expression in Liver Transplant Recipients as a Prognostic Indicator of Cytomegalovirus Disease. J Infect Dis. 2008;197: 25–33. doi: 10.1086/523652 18171281

13. Macedo C, Webber S a, Donnenberg AD, Popescu I, Hua Y, Green M, et al. EBV-specific CD8+ T cells from asymptomatic pediatric thoracic transplant patients carrying chronic high EBV loads display contrasting features: activated phenotype and exhausted function. J Immunol. 2011;186: 5854–5862. doi: 10.4049/jimmunol.1001024 21460204

14. Macedo C, Donnenberg A, Popescu I, Reyes J, Abu-Elmagd K, Shapiro R, et al. EBV-specific memory CD8+T cell phenotype and function in stable solid organ transplant patients. Transpl Immunol. 2005;14: 109–116. doi: 10.1016/j.trim.2005.02.001 15935301

15. Moran J, Dean J, De Oliveira A, O’Connell M, Riordan M, Connell J, et al. Increased levels of PD-1 expression on CD8 T cells in patients post-renal transplant irrespective of chronic high EBV viral load. Pediatr Transplant. 2013;17: 806–814. doi: 10.1111/petr.12156 24118875

16. Wilsdorf N, Eiz-Vesper B, Henke-Gendo C, Diestelhorst J, Oschlies I, Hussein K, et al. EBV-specific T-Cell immunity in pediatric solid organ graft recipients with posttransplantation lymphoproliferative disease. Transplantation. 2013;95: 247–255. doi: 10.1097/TP.0b013e318279968d 23222899

17. Pietersma FL, van Oosterom A, Ran L, Schuurman R, Meijer E, de Jonge N, et al. Adequate control of primary EBV infection and subsequent reactivations after cardiac transplantation in an EBV seronegative patient. Transpl Immunol. 2012;27: 48–51. doi: 10.1016/j.trim.2012.02.001 22342937

18. Neudoerfl C, Mueller BJ, Blume C, Daemen K, Stevanovic-Meyer M, Keil J, et al. The peripheral NK cell repertoire after kidney transplantation is modulated by different immunosuppressive drugs. Front Immunol. 2013;4: 1–14. doi: 10.3389/fimmu.2013.00001

19. Béziat V, Dalgard O, Asselah T, Halfon P, Bedossa P, Boudifa A, et al. CMV drives clonal expansion of NKG2C + NK cells expressing self-specific KIRs in chronic hepatitis patients. Eur J Immunol. 2012;42: 447–457. doi: 10.1002/eji.201141826 22105371

20. Achour A, Baychelier F, Besson C, Arnoux A, Marty M, Hannoun L, et al. Expansion of CMV-mediated NKG2C+ NK cells associates with the development of specific de novo malignancies in liver-transplanted patients. J Immunol. 2014;192: 503–11. doi: 10.4049/jimmunol.1301951 24307732

21. Baychelier F, Achour A, Nguyen S, Raphael M, Toubert A, Besson C, et al. Natural killer cell deficiency in patients with non-Hodgkin lymphoma after lung transplantation. J Hear Lung Transplant. 2015;34: 604–612.

22. Peraldi MN, Berrou J, Venot M, Chardiny V, Durrbach A, Vieillard V, et al. Natural killer lymphocytes are dysfunctional in kidney transplant recipients on diagnosis of cancer. Transplantation. 2015;99: 2422–2430. doi: 10.1097/tp.0000000000000792 26798861

23. Wiesmayr S, Webber SA, Macedo C, Popescu I, Smith L, Luce J, et al. Decreased NKp46 and NKG2D and elevated PD-1 are associated with altered NK-cell function in pediatric transplant patients with PTLD. Eur J Immunol. 2012;42: 541–550. doi: 10.1002/eji.201141832 22105417

24. Marcelin AG, Aaron L, Mateus C, Gyan E, Gorin I, Viard JP, et al. Rituximab therapy for HIV-associated Castleman disease. Blood. 2003;102: 2786–2788. doi: 10.1182/blood-2003-03-0951 12842986

25. Rickinson AB, Moss DJ. Human Cytotoxic T Lymphocyte Responses To Epstein Barr Virus Infection. Annu Rev Immunol. 1997;15: 405–431. doi: 10.1146/annurev.immunol.15.1.405 9143694

26. Woodberry T, Suscovich TJ, Henry LM, Davis JK, Frahm N, Walker BD, et al. Differential Targeting and Shifts in the Immunodominance of Epstein-Barr Virus–Specific CD8 and CD4 T Cell Responses during Acute and Persistent Infection. J Infect Dis 2005;192: 1513–1524. doi: 10.1086/491741 16206065

27. Leen ANN, Meij P, Redchenko I, Middeldorp J, Bloemena E, Rickinson A, et al. Differential Immunogenicity of Epstein-Barr Virus Latent-Cycle Proteins for Human CD4 ϩ T-Helper 1 Responses. J Virol. 2001;75: 8649–8659. doi: 10.1128/JVI.75.18.8649-8659.2001 11507210

28. Boyd A, Almeida JR, Darrah PA, Sauce D, Seder RA, Appay V, et al. Pathogen-Specific T Cell Polyfunctionality Is a Correlate of T Cell Efficacy and Immune Protection. PLoS One. 2015;10:1–18.

29. Warnes GR, Bolker B, Bonebakker L, Gentleman R, Liaw WHA, Lumley T, et al. gplots: Various R Programming Tools for Plotting Data. R package version 3.0.1; 2016. Database: CRAN [Internet]. Accessed: https://cran.r-project.org/web/packages/gplots.

30. Everitt BS, Landau S, Leese M, Stahl D. Agglomerative methods. In: Analysis Cluster. 5th ed. London, UK. John Wiley &Sons, Ltd. 2011.

31. Styles C, Paschos K, White R, Farrell P. The Cooperative Functions of the EBNA3 Proteins Are Central to EBV Persistence and Latency. Pathogens. 2018;7: 1–15.

32. Bhattacharjee S, Roy SG, Bose P, Saha A. Role of EBNA-3 family proteins in EBV associated B-cell lymphomagenesis. Front Microbiol. 2016;7: 1–16. doi: 10.3389/fmicb.2016.00001

33. Mollet L, Sadat-Sowti B, Duntze J, Leblond V, Bergeron F, Calvez V, et al. CD8(hi+)CD57+ T lymphocytes are enriched in antigen-specific T cells capable of down-modulating cytotoxic activity. Int Immunol. 1998;10: 311–323. doi: 10.1093/intimm/10.3.311 9576619

34. Jones K, Nourse JP, Morrison L, Nguyen-Van D, Moss DJ, Burrows SR, et al. Expansion of EBNA1-specific effector T cells in posttransplantation lymphoproliferative disorders. Blood. 2010;116: 2245–2252. doi: 10.1182/blood-2010-03-274076 20562330

35. Gasser O, Bihl FK, Wolbers M, Loggi E, Steffen I, Hirsch HH, et al. HIV patients developing primary CNS lymphoma lack EBV-specific CD4 + T cell function irrespective of absolute CD4+ T cell counts. PLoS Med. 2007;4: 556–561.

36. Heller KN, Arrey F, Steinherz P, Portlock C, Chadburn A, Kelly K, et al. Patients with Epstein Barr virus-positive lymphomas have decreased CD4 + T-cell responses to the viral nuclear antigen 1. Int J Cancer. 2008;123: 2824–2831. doi: 10.1002/ijc.23845 18781564

37. Calarota SA, Chiesa A, Zelini P, Comolli G, Minoli L, Baldanti F. Detection of Epstein-Barr virus-specific memory CD4+ T cells using a peptide-based cultured enzyme-linked immunospot assay. Immunology. 2013;139: 533–544. doi: 10.1111/imm.12106 23560877

38. Davis JE, Sherritt MA, Bharadwaj M, Morrison LE, Elliott SL, Kear LM, et al. Determining virological, serological and immunological parameters of EBV infection in the development of PTLD. Int Immunol. 2004;16: 983–989. doi: 10.1093/intimm/dxh099 15159377

39. Dasari V, Bhatt KH, Smith C, Khanna R. Designing an effective vaccine to prevent Epstein-Barr virus-associated diseases: challenges and opportunities. Expert Rev Vaccines. 2017;16: 377–390. doi: 10.1080/14760584.2017.1293529 28276306

40. O’Reilly RJ, Prockop S, Hasan AN, Koehne G, Doubrovina E. Virus-specific T-cell banks for “off the shelf” adoptive therapy of refractory infections. Bone Marrow Transplant. 2016;51: 1163–1172. doi: 10.1038/bmt.2016.17 27042851

41. Seyda M, Quante M, Uehara H, Slegtenhorst BR, Elkhal A, Tullius SG. Immunosenescence in renal transplantation. Curr Opin Organ Transplant. 2015;20: 417–423. doi: 10.1097/MOT.0000000000000210 26154914

42. Betjes MGH, Meijers RWJ, De Wit EA, Weimar W, Litjens NHR. Terminally differentiated CD8 + temra cells are associated with the risk for acute kidney allograft rejection. Transplantation. 2012;94: 63–69. doi: 10.1097/TP.0b013e31825306ff 22691956

43. Schaenman JM, Rossetti M, Sidwell T, Groysberg V, Sunga G, Korin Y, et al. Increased T cell immunosenescence and accelerated maturation phenotypes in older kidney transplant recipients. Hum Immunol. 2018;79: 659–667. doi: 10.1016/j.humimm.2018.06.006 29913200

44. Wang Y, Liu Y, Han R, Li Q, Yao Z, Niu W, et al. Monitoring of CD95 and CD38 expression in peripheral blood T lymphocytes during active human cytomegalovirus infection after orthotopic liver transplantation. J Gastroenterol Hepatol. 2010;25: 138–142. doi: 10.1111/j.1440-1746.2009.05966.x 19817952

45. Boleslawski E, Benothman S, Grabar S, Correia L, Podevin P, Chouzenoux S, et al. CD25, CD28 and CD38 expression in peripheral blood lymphocytes as a tool to predict acute rejection after liver transplantation. Clin Transplant. 2008;22: 494–501. doi: 10.1111/j.1399-0012.2008.00815.x 18565100

46. O’Byrne KJ, Dalgleish AG. Chronic immune activation and inflammation as the cause of malignancy. Br J Cancer. 2001;85: 473–483. doi: 10.1054/bjoc.2001.1943 11506482

47. Pike R, Thomas N, Workman S, Ambrose L, Guzman D, Sivakumaran S, et al. PD1-expressing T cell subsets modify the rejection risk in renal transplant patients. Front Immunol. 2016;7: 126. doi: 10.3389/fimmu.2016.00126 27148254

48. Pittari G, Vago L, Festuccia M, Bonini C, Mudawi D, Giaccone L, et al. Restoring Natural Killer Cell Immunity against Multiple Myeloma in the Era of New Drugs. Front Immunol. 2017;8: 1444. doi: 10.3389/fimmu.2017.01444 29163516

49. Liu Y, Cheng Y, Xu Y, Wang Z, Du X, Li C, et al. Increased expression of programmed cell death protein 1 on NK cells inhibits NK-cell-mediated anti-tumor function and indicates poor prognosis in digestive cancers. Oncogene. 2017;36: 6143–6153. doi: 10.1038/onc.2017.209 28692048

50. Pesce S, Greppi M, Tabellini G, Rampinelli F, Parolini S, Olive D, et al. Identification of a subset of human natural killer cells expressing high levels of programmed death 1: A phenotypic and functional characterization. J Allergy Clin Immunol. 2017;139: 335–346. doi: 10.1016/j.jaci.2016.04.025 27372564

51. Beldi-Ferchiou A, Lambert M, Dogniaux S, Vély F, Vivier E, Olive D, et al. PD-1 mediates functional exhaustion of activated NK cells in patients with Kaposi sarcoma. Oncotarget. 2016;7: 72961–72977. doi: 10.18632/oncotarget.12150 27662664

52. Mederacke YS, Vondran FW, Kollrich S, Schulde E, Schmitt R, Manns MP, et al. Transient increase of activated regulatory T cells early after kidney transplantation. Sci Rep. 2019;9: 1–12. doi: 10.1038/s41598-018-37186-2

53. Andreola G, Chittenden M, Shaffer J, Cosimi AB, Kawai T, Cotter P, et al. Mechanisms of Donor-Specific Tolerance in Recipients of Haploidentical Combined Bone Marrow/Kidney Transplantation. Am J Transplant. 2011;11: 1236–1247. doi: 10.1111/j.1600-6143.2011.03566.x 21645255


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