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Control of Murine Cytomegalovirus Infection by γδ T Cells


Cytomegalovirus is a clinically important pathogen. While infection in hosts with a functional immune system is usually asymptomatic, the virus can cause significant morbidity and mortality in individuals with an immature or suppressed immune system. The virus causes severe clinical complication in transplant recipients and congenital CMV infections are the most common infectious cause of neurological disorders in children. Multiple layers of innate and adoptive immunity are involved in the control of CMV and single deficiencies of one immune cell type can be compensated by other immune cells. Expansions of γδ T lymphocytes, which are regarded as innate-like cells with adaptive-like potential, have been shown to be associated with CMV infections in human transplant patients and neonates. Their role in protective immunity against CMV has been unclear, however. Here we show direct evidence in the murine CMV model (MCMV) that γδ T lymphocytes can provide protection against a lethal MCMV infection in the absence of any other cells of the adoptive immune system. Upon infection, γδ T lymphocytes undergo a significant expansion and a prominent and long-lasting phenotypic change. These findings have implications for the development of new cellular therapy regimens in CMV infections in the transplant setting that should be evaluated in the future.


Vyšlo v časopise: Control of Murine Cytomegalovirus Infection by γδ T Cells. PLoS Pathog 11(2): e32767. doi:10.1371/journal.ppat.1004481
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004481

Souhrn

Cytomegalovirus is a clinically important pathogen. While infection in hosts with a functional immune system is usually asymptomatic, the virus can cause significant morbidity and mortality in individuals with an immature or suppressed immune system. The virus causes severe clinical complication in transplant recipients and congenital CMV infections are the most common infectious cause of neurological disorders in children. Multiple layers of innate and adoptive immunity are involved in the control of CMV and single deficiencies of one immune cell type can be compensated by other immune cells. Expansions of γδ T lymphocytes, which are regarded as innate-like cells with adaptive-like potential, have been shown to be associated with CMV infections in human transplant patients and neonates. Their role in protective immunity against CMV has been unclear, however. Here we show direct evidence in the murine CMV model (MCMV) that γδ T lymphocytes can provide protection against a lethal MCMV infection in the absence of any other cells of the adoptive immune system. Upon infection, γδ T lymphocytes undergo a significant expansion and a prominent and long-lasting phenotypic change. These findings have implications for the development of new cellular therapy regimens in CMV infections in the transplant setting that should be evaluated in the future.


Zdroje

1. Mach M, Wiegers A-K, Spindler N, Winkler T (2013) Protective Humoral Immunity. In: Reddehase MJ, editor. Cytomegaloviruses: From Molecular Pathogenesis to Intervention. 1. edition ed: Caister Academic Press.

2. Reddehase MJ (2002) Antigens and immunoevasins: opponents in cytomegalovirus immune surveillance. Nat Rev Immunol 2: 831–844. doi: 10.1038/nri932 12415307

3. Polić B, Hengel H, Krmpotić A, Trgovcich J, Pavić I, et al. (1998) Hierarchical and redundant lymphocyte subset control precludes cytomegalovirus replication during latent infection. J Exp Med 188: 1047–1054. doi: 10.1084/jem.188.6.1047 9743523

4. Boeckh M, Geballe AP (2011) Cytomegalovirus: pathogen, paradigm, and puzzle. J Clin Invest 121: 1673–1680. doi: 10.1172/JCI45449 21659716

5. Boeckh M, Ljungman P (2009) How we treat cytomegalovirus in hematopoietic cell transplant recipients. Blood 113: 5711–5719. doi: 10.1182/blood-2008-10-143560 19299333

6. Kurz S, Steffens HP, Mayer A, Harris JR, Reddehase MJ (1997) Latency versus persistence or intermittent recurrences: evidence for a latent state of murine cytomegalovirus in the lungs. J Virol 71: 2980–2987. 9060657

7. Reddehase MJ, Mutter W, Münch K, Bühring HJ, Koszinowski UH (1987) CD8-positive T lymphocytes specific for murine cytomegalovirus immediate-early antigens mediate protective immunity. J Virol 61: 3102–3108. 3041033

8. Reddehase MJ, Jonjic S, Weiland F, Mutter W, Koszinowski UH (1988) Adoptive immunotherapy of murine cytomegalovirus adrenalitis in the immunocompromised host: CD4-helper-independent antiviral function of CD8-positive memory T lymphocytes derived from latently infected donors. J Virol 62: 1061–1065. 2828654

9. Feuchtinger T, Opherk K, Bethge WA, Topp MS, Schuster FR, et al. (2010) Adoptive transfer of pp65-specific T cells for the treatment of chemorefractory cytomegalovirus disease or reactivation after haploidentical and matched unrelated stem cell transplantation. Blood 116: 4360–4367. doi: 10.1182/blood-2010-01-262089 20625005

10. Jonjic S, Mutter W, Weiland F, Reddehase MJ, Koszinowski UH (1989) Site-restricted persistent cytomegalovirus infection after selective long-term depletion of CD4+ T lymphocytes. J Exp Med 169: 1199–1212. doi: 10.1084/jem.169.4.1199 2564415

11. Walton SM, Mandaric S, Torti N, Zimmermann A, Hengel H, et al. (2011) Absence of cross-presenting cells in the salivary gland and viral immune evasion confine cytomegalovirus immune control to effector CD4 T cells. PLoS Pathog 7: e1002214. doi: 10.1371/journal.ppat.1002214 21901102

12. Hammoud B, Schmueck M, Fischer AM, Fuehrer H, Park S-J, et al. (2013) HCMV-specific T-cell therapy: do not forget supply of help. J Immunother 36: 93–101. doi: 10.1097/CJI.0b013e31827b87cc 23377662

13. Wirtz N, Schader SI, Holtappels R, Simon CO, Lemmermann NAW, et al. (2008) Polyclonal cytomegalovirus-specific antibodies not only prevent virus dissemination from the portal of entry but also inhibit focal virus spread within target tissues. Med Microbiol Immunol 197: 151–158. doi: 10.1007/s00430-008-0095-0 18365251

14. Klenovsek K, Weisel F, Schneider A, Appelt U, Jonjic S, et al. (2007) Protection from CMV infection in immunodeficient hosts by adoptive transfer of memory B cells. Blood 110: 3472–3479. doi: 10.1182/blood-2007-06-095414 17656648

15. Jonjic S, Pavić I, Polić B, Crnković I, Lucin P, et al. (1994) Antibodies are not essential for the resolution of primary cytomegalovirus infection but limit dissemination of recurrent virus. J Exp Med 179: 1713–1717. doi: 10.1084/jem.179.5.1713 8163949

16. Farrell HE, Shellam GR (1991) Protection against murine cytomegalovirus infection by passive transfer of neutralizing and non-neutralizing monoclonal antibodies. J Gen Virol 72 (Pt 1): 149–156. doi: 10.1099/0022-1317-72-1-149 1846643

17. Jonjic S, Pavić I, Lucin P, Rukavina D, Koszinowski UH (1990) Efficacious control of cytomegalovirus infection after long-term depletion of CD8+ T lymphocytes. J Virol 64: 5457–5464. 1976821

18. French AR, Pingel JT, Wagner M, Bubic I, Yang L, et al. (2004) Escape of mutant double-stranded DNA virus from innate immune control. Immunity 20: 747–756. doi: 10.1016/j.immuni.2004.05.006 15189739

19. Holtappels R, Podlech J, Grzimek NK, Thomas D, Pahl-Seibert MF, et al. (2001) Experimental preemptive immunotherapy of murine cytomegalovirus disease with CD8 T-cell lines specific for ppM83 and pM84, the two homologs of human cytomegalovirus tegument protein ppUL83 (pp65). J Virol 75: 6584–6600. doi: 10.1128/JVI.75.14.6584-6600.2001 11413326

20. Jordan S, Krause J, Prager A, Mitrovic M, Jonjic S, et al. (2011) Virus Progeny of Murine Cytomegalovirus Bacterial Artificial Chromosome pSM3fr Show Reduced Growth in Salivary Glands due to a Fixed Mutation of MCK-2. J Virol 85: 10346–10353. doi: 10.1128/JVI.00545-11 21813614

21. Vantourout P, Hayday A (2013) Six-of-the-best: unique contributions of γδ T cells to immunology. Nat Rev Immunol 13: 88–100. doi: 10.1038/nri3384 23348415

22. Ribot JC, Debarros A, Pang DJ, Neves JF, Peperzak V, et al. (2009) CD27 is a thymic determinant of the balance between interferon-gamma- and interleukin 17-producing gammadelta T cell subsets. Nat Immunol 10: 427–436. doi: 10.1038/ni.1717 19270712

23. Carding SR, Egan PJ (2002) Gammadelta T cells: functional plasticity and heterogeneity. Nat Rev Immunol 2: 336–345. doi: 10.1038/nri797 12033739

24. Kamphuis E, Junt T, Waibler Z, Förster R, Kalinke U (2006) Type I interferons directly regulate lymphocyte recirculation and cause transient blood lymphopenia. Blood 108: 3253–3261. doi: 10.1182/blood-2006-06-027599 16868248

25. Jamieson AM, Diefenbach A, McMahon CW, Xiong N, Carlyle JR, et al. (2002) The role of the NKG2D immunoreceptor in immune cell activation and natural killing. Immunity 17: 19–29. doi: 10.1016/S1074-7613(02)00333-3 12150888

26. Gravestein LA, Nieland JD, Kruisbeek AM, Borst J (1995) Novel mAbs reveal potent co-stimulatory activity of murine CD27. Int Immunol 7: 551–557. doi: 10.1093/intimm/7.4.551 7547681

27. Déchanet J, Merville P, Lim A, Retière C, Pitard V, et al. (1999) Implication of gammadelta T cells in the human immune response to cytomegalovirus. J Clin Invest 103: 1437–1449. doi: 10.1172/JCI5409 10330426

28. Heilig JS, Tonegawa S (1986) Diversity of murine gamma genes and expression in fetal and adult T lymphocytes. Nature 322: 836–840. doi: 10.1038/322836a0 2943999

29. Balthesen M, Messerle M, Reddehase MJ (1993) Lungs are a major organ site of cytomegalovirus latency and recurrence. J Virol 67: 5360–5366. 8394453

30. Turchinovich G, Pennington DJ (2011) T cell receptor signalling in γδ cell development: strength isn't everything. Trends Immunol 32: 567–573. doi: 10.1016/j.it.2011.09.005 22056207

31. Sun JC, Beilke JN, Lanier LL (2009) Adaptive immune features of natural killer cells. Nature 457: 557–561. doi: 10.1038/nature07665 19136945

32. Scheper W, van Dorp S, Kersting S, Pietersma F, Lindemans C, et al. (2013) γδT cells elicited by CMV reactivation after allo-SCT cross-recognize CMV and leukemia. Leukemia 27: 1328–1338. doi: 10.1038/leu.2012.374 23277330

33. Dieli F, Poccia F, Lipp M, Sireci G, Caccamo N, et al. (2003) Differentiation of effector/memory Vdelta2 T cells and migratory routes in lymph nodes or inflammatory sites. J Exp Med 198: 391–397. doi: 10.1084/jem.20030235 12900516

34. Carding SR, Allan W, Kyes S, Hayday A, Bottomly K, et al. (1990) Late dominance of the inflammatory process in murine influenza by gamma/delta + T cells. J Exp Med 172: 1225–1231. doi: 10.1084/jem.172.4.1225 2145388

35. Alejenef A, Pachnio A, Halawi M, Christmas SE, Moss PA, et al. (2014) Cytomegalovirus drives Vdelta2neg gammadelta T cell inflation in many healthy virus carriers with increasing age. Clin Exp Immunol 176: 418–428. doi: 10.1111/cei.12297 24547915

36. Willcox CR, Pitard V, Netzer S, Couzi L, Salim M, et al. (2012) Cytomegalovirus and tumor stress surveillance by binding of a human γδ T cell antigen receptor to endothelial protein C receptor. Nat Immunol 13: 872–879. doi: 10.1038/ni.2394 22885985

37. Dyugovskaya L, Hirsh M, Ginsburg H (2003) Phenotypic profile and functional characterization of rat lymph node-derived gammadelta T cells: implication in the immune response to cytomegalovirus. Immunology 108: 129–136. doi: 10.1046/j.1365-2567.2003.01568.x 12562320

38. Ninomiya T, Takimoto H, Matsuzaki G, Hamano S, Yoshida H, et al. (2000) Vgamma1+ gammadelta T cells play protective roles at an early phase of murine cytomegalovirus infection through production of interferon-gamma. Immunology 99: 187–194. doi: 10.1046/j.1365-2567.2000.00938.x 10692035

39. Halary F, Pitard V, Dlubek D, Krzysiek R, de la Salle H, et al. (2005) Shared reactivity of Vdelta2neg gamma delta T cells against cytomegalovirus-infected cells and tumor intestinal epithelial cells. J Exp Med 201: 1567–1578. doi: 10.1084/jem.20041851 15897274

40. Lafarge X, Merville P, Cazin MC, Bergé F, Potaux L, et al. (2001) Cytomegalovirus infection in transplant recipients resolves when circulating gammadelta T lymphocytes expand, suggesting a protective antiviral role. J Infect Dis 184: 533–541. doi: 10.1086/322843 11494158

41. Knight A, Madrigal AJ, Grace S, Sivakumaran J, Kottaridis P, et al. (2010) The role of Vδ2-negative γδ T cells during cytomegalovirus reactivation in recipients of allogeneic stem cell transplantation. Blood 116: 2164–2172. doi: 10.1182/blood-2010-01-255166 20576814

42. Vermijlen D, Brouwer M, Donner C, Liesnard C, Tackoen M, et al. (2010) Human cytomegalovirus elicits fetal gammadelta T cell responses in utero. J Exp Med 207: 807–821. doi: 10.1084/jem.20090348 20368575

43. Handgretinger R (2012) Negative depletion of CD3(+) and TcRαβ(+) T cells. Curr Opin Hematol 19: 434–439. doi: 10.1097/MOH.0b013e3283582340 22914586

44. Godder KT, Henslee-Downey PJ, Mehta J, Park BS, Chiang K-Y, et al. (2007) Long term disease-free survival in acute leukemia patients recovering with increased gammadelta T cells after partially mismatched related donor bone marrow transplantation. Bone Marrow Transplant 39: 751–757. doi: 10.1038/sj.bmt.1705650 17450185

45. Chen J, Trounstine M, Alt FW, Young F, Kurahara C, et al. (1993) Immunoglobulin gene rearrangement in B cell deficient mice generated by targeted deletion of the JH locus. Int Immunol 5: 647–656. doi: 10.1093/intimm/5.6.647 8347558

46. Fung-Leung WP, Schilham MW, Rahemtulla A, Kündig TM, Vollenweider M, et al. (1991) CD8 is needed for development of cytotoxic T cells but not helper T cells. Cell 65: 443–449. doi: 10.1016/0092-8674(91)90462-8 1673361

47. Podlech J, Holtappels R, Grzimek NKA, Reddehase MJ (2002) Animal models: Murine cytomegalovirus. In: Stefan H. E KDK, editor. Methods in Microbiology: Academic Press. pp. 493–525.

48. Cobbold SP, Jayasuriya A, Nash A, Prospero TD, Waldmann H (1984) Therapy with monoclonal antibodies by elimination of T-cell subsets in vivo. Nature 312: 548–551. doi: 10.1038/312548a0 6150440

49. Alamyar E, Duroux P, Lefranc MP, Giudicelli V (2012) IMGT((R)) tools for the nucleotide analysis of immunoglobulin (IG) and T cell receptor (TR) V-(D)-J repertoires, polymorphisms, and IG mutations: IMGT/V-QUEST and IMGT/HighV-QUEST for NGS. Methods Mol Biol 882: 569–604. doi: 10.1007/978-1-61779-842-9_32 22665256

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Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

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