Absence of Cross-Presenting Cells in the Salivary Gland and Viral Immune Evasion Confine Cytomegalovirus Immune Control to Effector CD4 T Cells

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Horizontal transmission of cytomegaloviruses (CMV) occurs via prolonged excretion from mucosal surfaces. We used murine CMV (MCMV) infection to investigate the mechanisms of immune control in secretory organs. CD4 T cells were crucial to cease MCMV replication in the salivary gland (SG) via direct secretion of IFNγ that initiated antiviral signaling on non-hematopoietic cells. In contrast, CD4 T cell helper functions for CD8 T cells or B cells were dispensable. Despite SG-resident MCMV-specific CD8 T cells being able to produce IFNγ, the absence of MHC class I molecules on infected acinar glandular epithelial cells due to viral immune evasion, and the paucity of cross-presenting antigen presenting cells (APCs) prevented their local activation. Thus, local activation of MCMV-specific T cells is confined to the CD4 subset due to exclusive presentation of MCMV-derived antigens by MHC class II molecules on bystander APCs, resulting in IFNγ secretion interfering with viral replication in cells of non-hematopoietic origin.

Vyšlo v časopise: 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(8): e32767. doi:10.1371/journal.ppat.1002214
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1002214

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Zdroje

1. MocarskiESShenkTPassRF 2007 Cytomegaloviruses; HowleyDKKaPM Philadelphia Lippincott, Williams & Wilkins

2. BoppanaSBFowlerKB 2007 Persistence in the population: epidemiology and transmisson. Arvin AC-FGMocarskiEMoorePSRoizmanBWhitleyRYamanishiK Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis Cambridge Cambridge University Press 2011/02/25 ed.

3. BrittW 2007 Virus entry into host, establishment of infection, spread in host, mechanisms of tissue damage. Arvin AC-FGMocarskiEMoorePSRoizmanBWhitleyRYamanishiK Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis Cambridge Cambridge University Press 2011/02/25 ed.

4. CampbellAECavanaughVJSlaterJS 2008 The salivary glands as a privileged site of cytomegalovirus immune evasion and persistence. Med Microbiol Immunol 197 205 213

5. JonjicSMutterWWeilandFReddehaseMJKoszinowskiUH 1989 Site-restricted persistent cytomegalovirus infection after selective long-term depletion of CD4+ T lymphocytes. J Exp Med 169 1199 1212

6. LucinPPavicIPolicBJonjicSKoszinowskiUH 1992 Gamma interferon-dependent clearance of cytomegalovirus infection in salivary glands. J Virol 66 1977 1984

7. PavicIPolicBCrnkovicILucinPJonjicS 1993 Participation of endogenous tumour necrosis factor alpha in host resistance to cytomegalovirus infection. J Gen Virol 74 Pt10 2215 2223

8. WaltonSMWyrschPMunksMWZimmermannAHengelH 2008 The dynamics of mouse cytomegalovirus-specific CD4 T cell responses during acute and latent infection. J Immunol 181 1128 1134

9. ArensRWangPSidneyJLoewendorfASetteA 2008 Cutting edge: murine cytomegalovirus induces a polyfunctional CD4 T cell response. J Immunol 180 6472 6476

10. JonjicSPavicILucinPRukavinaDKoszinowskiUH 1990 Efficacious control of cytomegalovirus infection after long-term depletion of CD8+ T lymphocytes. J Virol 64 5457 5464

11. PolicBJonjicSPavicICrnkovicIZoricaI 1996 Lack of MHC class I complex expression has no effect on spread and control of cytomegalovirus infection in vivo. J Gen Virol 77 Pt 2 217 225

12. JonjicSPavicIPolicBCrnkovicILucinP 1994 Antibodies are not essential for the resolution of primary cytomegalovirus infection but limit dissemination of recurrent virus. J Exp Med 179 1713 1717

13. ScalzoAAManzurMForbesCABrownMGShellamGR 2005 NK gene complex haplotype variability and host resistance alleles to murine cytomegalovirus in wild mouse populations. Immunol Cell Biol 83 144 149

14. BrownMGScalzoAAStoneLRClarkPYDuY 2001 Natural killer gene complex (Nkc) allelic variability in inbred mice: evidence for Nkc haplotypes. Immunogenetics 53 584 591

15. CasazzaJPBettsMRPriceDAPrecopioMLRuffLE 2006 Acquisition of direct antiviral effector functions by CMV-specific CD4+ T lymphocytes with cellular maturation. J Exp Med 203 2865 2877

16. KlenovsekKWeiselFSchneiderAAppeltUJonjicS 2007 Protection from CMV infection in immunodeficient hosts by adoptive transfer of memory B cells. Blood 110 3472 3479

17. MunksMWPintoAKDoomCMHillAB 2007 Viral interference with antigen presentation does not alter acute or chronic CD8 T cell immunodominance in murine cytomegalovirus infection. J Immunol 178 7235 7241

18. SierroSRothkopfRKlenermanP 2005 Evolution of diverse antiviral CD8+ T cell populations after murine cytomegalovirus infection. Eur J Immunol 35 1113 1123

19. WieselMWaltonSRichterKOxeniusA 2009 Virus-specific CD8 T cells: activation, differentiation and memory formation. APMIS 117 356 381

20. SnyderCMLoewendorfABonnettELCroftMBenedictCA 2009 CD4+ T cell help has an epitope-dependent impact on CD8+ T cell memory inflation during murine cytomegalovirus infection. J Immunol 183 3932 3941

21. ReddehaseMJJonjicSWeilandFMutterWKoszinowskiUH 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

22. WaltonSMTortiNMandaricSOxeniusA 2011 T cell help permits memory CD8(+) T cell inflation during cytomegalovirus latency. Eur J Immunol. May 17 doi:10.1002/eji.201141575

23. CavanaughVJDengYBirkenbachMPSlaterJSCampbellAE 2003 Vigorous innate and virus-specific cytotoxic T-lymphocyte responses to murine cytomegalovirus in the submaxillary salivary gland. J Virol 77 1703 1717

24. NakanishiYLuBGerardCIwasakiA 2009 CD8(+) T lymphocyte mobilization to virus-infected tissue requires CD4(+) T-cell help. Nature 462 510 513

25. LuXPintoAKKellyAMChoKSHillAB 2006 Murine cytomegalovirus interference with antigen presentation contributes to the inability of CD8 T cells to control virus in the salivary gland. J Virol 80 4200 4202

26. RedpathSAnguloAGascoigneNRGhazalP 1999 Murine cytomegalovirus infection down-regulates MHC class II expression on macrophages by induction of IL-10. J Immunol 162 6701 6707

27. HeiseMTConnickMVirginHWt 1998 Murine cytomegalovirus inhibits interferon gamma-induced antigen presentation to CD4 T cells by macrophages via regulation of expression of major histocompatibility complex class II-associated genes. J Exp Med 187 1037 1046

28. MathysSSchroederTEllwartJKoszinowskiUHMesserleM 2003 Dendritic cells under influence of mouse cytomegalovirus have a physiologic dual role: to initiate and to restrict T cell activation. J Infect Dis 187 988 999

29. DoomCMHillAB 2008 MHC class I immune evasion in MCMV infection. Med Microbiol Immunol 197 191 204

30. HildnerKEdelsonBTPurthaWEDiamondMMatsushitaH 2008 Batf3 deficiency reveals a critical role for CD8alpha+ dendritic cells in cytotoxic T cell immunity. Science 322 1097 1100

31. del RioMLBernhardtGRodriguez-BarbosaJIForsterR 2010 Development and functional specialization of CD103+ dendritic cells. Immunol Rev 234 268 281

32. BedouiSWhitneyPGWaithmanJEidsmoLWakimL 2009 Cross-presentation of viral and self antigens by skin-derived CD103+ dendritic cells. Nat Immunol 10 488 495

33. RuedlCStorniTLechnerFBachiTBachmannMF 2002 Cross-presentation of virus-like particles by skin-derived CD8(-) dendritic cells: a dispensable role for TAP. Eur J Immunol 32 818 825

34. WagnerMGutermannAPodlechJReddehaseMJKoszinowskiUH 2002 Major histocompatibility complex class I allele-specific cooperative and competitive interactions between immune evasion proteins of cytomegalovirus. J Exp Med 196 805 816

35. PearceELShedlockDJShenH 2004 Functional characterization of MHC class II-restricted CD8+CD4- and CD8-CD4- T cell responses to infection in CD4-/- mice. J Immunol 173 2494 2499

36. TyznikAJSunJCBevanMJ 2004 The CD8 population in CD4-deficient mice is heavily contaminated with MHC class II-restricted T cells. J Exp Med 199 559 565

37. WirtzNSchaderSIHoltappelsRSimonCOLemmermannNA 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

38. LucinPJonjicSMesserleMPolicBHengelH 1994 Late phase inhibition of murine cytomegalovirus replication by synergistic action of interferon-gamma and tumour necrosis factor. J Gen Virol 75 Pt1 101 110

39. BukowskiJFWelshRM 1985 Inability of interferon to protect virus-infected cells against lysis by natural killer (NK) cells correlates with NK cell-mediated antiviral effects in vivo. J Immunol 135 3537 3541

40. OrangeJSWangBTerhorstCBironCA 1995 Requirement for natural killer cell-produced interferon gamma in defense against murine cytomegalovirus infection and enhancement of this defense pathway by interleukin 12 administration. J Exp Med 182 1045 1056

41. OrangeJSBironCA 1996 An absolute and restricted requirement for IL-12 in natural killer cell IFN-gamma production and antiviral defense. Studies of natural killer and T cell responses in contrasting viral infections. J Immunol 156 1138 1142

42. TessmerMSReillyECBrossayL 2011 Salivary gland NK cells are phenotypically and functionally unique. PLoS Pathog 7 e1001254

43. BabicMPyzikMZafirovaBMitrovicMButoracV 2010 Cytomegalovirus immunoevasin reveals the physiological role of "missing self" recognition in natural killer cell dependent virus control in vivo. J Exp Med 207 2663 2673

44. AndrewsDMEstcourtMJAndoniouCEWikstromMEKhongA 2010 Innate immunity defines the capacity of antiviral T cells to limit persistent infection. J Exp Med 207 1333 1343

45. KontgenFSussGStewartCSteinmetzMBluethmannH 1993 Targeted disruption of the MHC class II Aa gene in C57BL/6 mice. Int Immunol 5 957 964

46. RahemtullaAFung-LeungWPSchilhamMWKundigTMSambharaSR 1991 Normal development and function of CD8+ cells but markedly decreased helper cell activity in mice lacking CD4. Nature 353 180 184

47. GuHZouYRRajewskyK 1993 Independent control of immunoglobulin switch recombination at individual switch regions evidenced through Cre-loxP-mediated gene targeting. Cell 73 1155 1164

48. MarinoMWDunnAGrailDIngleseMNoguchiY 1997 Characterization of tumor necrosis factor-deficient mice. Proc Natl Acad Sci U S A 94 8093 8098

49. KagiDLedermannBBurkiKSeilerPOdermattB 1994 Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice. Nature 369 31 37

50. CobboldSPJayasuriyaANashAProsperoTDWaldmannH 1984 Therapy with monoclonal antibodies by elimination of T-cell subsets in vivo. Nature 312 548 551

51. StorniTBachmannMF 2004 Loading of MHC class I and II presentation pathways by exogenous antigens: a quantitative in vivo comparison. J Immunol 172 6129 6135

52. HasanMKrmpoticARuzsicsZBubicILenacT 2005 Selective down-regulation of the NKG2D ligand H60 by mouse cytomegalovirus m155 glycoprotein. J Virol 79 2920 2930

53. BruneWHengelHKoszinowskiUH 2001 A mouse model for cytomegalovirus infection. Curr Protoc Immunol Chapter 19 Unit 19 17

54. AltmanJDMossPAGoulderPJBarouchDHMcHeyzer-WilliamsMG 1996 Phenotypic analysis of antigen-specific T lymphocytes. Science 274 94 96

55. JollerNSporriRHilbiHOxeniusA 2007 Induction and protective role of antibodies in Legionella pneumophila infection. Eur J Immunol 37 3414 3423