1887

Abstract

Expansion of the CD8 T-cell memory pool, also known as ‘memory inflation’, for certain but not all viral epitopes in latently infected host tissues is a special feature of the immune response to cytomegalovirus. The L-presented murine cytomegalovirus (mCMV) immediate–early (IE) 1 peptide is the prototype of an epitope that is associated with memory inflation. Based on the detection of IE1 transcripts in latently infected lungs it was previously proposed that episodes of viral gene expression and antigenic activity due to desilencing of a limited number of viral genes may drive epitope-specific memory inflation. This would imply direct antigen presentation through latently infected host tissue cells rather than cell death-associated cross-presentation of viral antigens derived from productively infected cells through uninfected, professional antigen-presenting cells (profAPCs). To address the role of bone marrow-derived profAPCs in CD8 T-cell priming and memory to mCMV, we have used here a combined sex-mismatched and MHC class-I mismatched dual-marker bone marrow chimera model in which presentation of the IE1 epitope is restricted to donor-derived L cells of haematopoietic differentiation lineages. Successful CD8 T-cell priming specific for the L- and D-presented inflationary epitopes IE1 and m164, respectively, but selective failure in IE1 epitope-specific memory inflation in these chimeras indicates different modes of antigen presentation involved in CD8 T-cell priming and memory inflation. These data suggest that memory inflation during mCMV latency requires expression of the epitope-presenting MHC class-I molecule by latently infected non-haematopoietic host tissue cells and thus predicts a role for direct antigen presentation in memory inflation.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.031815-0
2011-09-01
2019-10-15
Loading full text...

Full text loading...

/deliver/fulltext/jgv/92/9/1994.html?itemId=/content/journal/jgv/10.1099/vir.0.031815-0&mimeType=html&fmt=ahah

References

  1. Allan R. S. , Smith C. M. , Belz G. T. , van Lint A. L. , Wakim L. M. , Heath W. R. , Carbone F. R. . ( 2003; ). Epidermal viral immunity induced by CD8α+ dendritic cells but not by Langerhans cells. . Science 301:, 1925–1928. [CrossRef].[PubMed].
    [Google Scholar]
  2. Alterio de Goss M. , Holtappels R. , Steffens H.-P. , Podlech J. , Angele P. , Dreher L. , Thomas D. , Reddehase M. J. . ( 1998; ). Control of cytomegalovirus in bone marrow transplantation chimeras lacking the prevailing antigen-presenting molecule in recipient tissues rests primarily on recipient-derived CD8 T cells. . J Virol 72:, 7733–7744.[PubMed].
    [Google Scholar]
  3. Andrews D. M. , Andoniou C. E. , Granucci F. , Ricciardi-Castagnoli P. , Degli-Esposti M. A. . ( 2001; ). Infection of dendritic cells by murine cytomegalovirus induces functional paralysis. . Nat Immunol 2:, 1077–1084. [CrossRef].[PubMed].
    [Google Scholar]
  4. Arens R. , Wang P. , Sidney J. , Loewendorf A. , Sette A. , Schoenberger S. P. , Peters B. , Benedict C. A. . ( 2008; ). Cutting edge: murine cytomegalovirus induces a polyfunctional CD4 T cell response. . J Immunol 180:, 6472–6476.[PubMed].[CrossRef]
    [Google Scholar]
  5. Balthesen M. , Messerle M. , Reddehase M. J. . ( 1993; ). Lungs are a major organ site of cytomegalovirus latency and recurrence. . J Virol 67:, 5360–5366.[PubMed].
    [Google Scholar]
  6. Belz G. T. , Smith C. M. , Eichner D. , Shortman K. , Karupiah G. , Carbone F. R. , Heath W. R. . ( 2004; ). Cutting edge: conventional CD8α+ dendritic cells are generally involved in priming CTL immunity to viruses. . J Immunol 172:, 1996–2000.[PubMed].[CrossRef]
    [Google Scholar]
  7. Benedict C. A. , Loewendorf A. , Garcia Z. , Blazar B. R. , Janssen E. M. . ( 2008; ). Dendritic cell programming by cytomegalovirus stunts naive T cell responses via the PD-L1/PD-1 pathway. . J Immunol 180:, 4836–4847.[PubMed].[CrossRef]
    [Google Scholar]
  8. Böhm V. , Simon C. O. , Podlech J. , Seckert C. K. , Gendig D. , Deegen P. , Gillert-Marien D. , Lemmermann N. A. W. , Holtappels R. , Reddehase M. J. . ( 2008; ). The immune evasion paradox: immunoevasins of murine cytomegalovirus enhance priming of CD8 T cells by preventing negative feedback regulation. . J Virol 82:, 11637–11650. [CrossRef].[PubMed].
    [Google Scholar]
  9. Campbell A. E. , Cavanaugh V. J. , Slater J. S. . ( 2008; ). The salivary glands as a privileged site of cytomegalovirus immune evasion and persistence. . Med Microbiol Immunol (Berl) 197:, 205–213. [CrossRef].[PubMed].
    [Google Scholar]
  10. Dalod M. , Hamilton T. , Salomon R. , Salazar-Mather T. P. , Henry S. C. , Hamilton J. D. , Biron C. A. . ( 2003; ). Dendritic cell responses to early murine cytomegalovirus infection: subset functional specialization and differential regulation by interferon α/β. . J Exp Med 197:, 885–898. [CrossRef].[PubMed].
    [Google Scholar]
  11. Del Val M. , Schlicht H.-J. , Ruppert T. , Reddehase M. J. , Koszinowski U. H. . ( 1991; ). Efficient processing of an antigenic sequence for presentation by MHC class I molecules depends on its neighboring residues in the protein. . Cell 66:, 1145–1153. [CrossRef].[PubMed].
    [Google Scholar]
  12. den Haan J. M. , Bevan M. J. . ( 2001; ). Antigen presentation to CD8+ T cells: cross-priming in infectious diseases. . Curr Opin Immunol 13:, 437–441. [CrossRef].[PubMed].
    [Google Scholar]
  13. Derbinski J. , Kyewski B. . ( 2010; ). How thymic antigen presenting cells sample the body’s self-antigens. . Curr Opin Immunol 22:, 592–600. [CrossRef].[PubMed].
    [Google Scholar]
  14. Doom C. M. , Hill A. B. . ( 2008; ). MHC class I immune evasion in MCMV infection. . Med Microbiol Immunol (Berl) 197:, 191–204. [CrossRef].[PubMed].
    [Google Scholar]
  15. Falk K. , Rötzschke O. , Rammensee H.-G. . ( 1990; ). Cellular peptide composition governed by major histocompatibility complex class I molecules. . Nature 348:, 248–251. [CrossRef].[PubMed].
    [Google Scholar]
  16. Gold M. C. , Munks M. W. , Wagner M. , Koszinowski U. H. , Hill A. B. , Fling S. P. . ( 2002; ). The murine cytomegalovirus immunomodulatory gene m152 prevents recognition of infected cells by M45-specific CTL but does not alter the immunodominance of the M45-specific CD8 T cell response in vivo . . J Immunol 169:, 359–365.[PubMed].[CrossRef]
    [Google Scholar]
  17. Grzimek N. K. A. , Dreis D. , Schmalz S. , Reddehase M. J. . ( 2001; ). Random, asynchronous, and asymmetric transcriptional activity of enhancer-flanking major immediate-early genes ie1/3 and ie2 during murine cytomegalovirus latency in the lungs. . J Virol 75:, 2692–2705. [CrossRef].[PubMed].
    [Google Scholar]
  18. Hansen T. H. , Bouvier M. . ( 2009; ). MHC class I antigen presentation: learning from viral evasion strategies. . Nat Rev Immunol 9:, 503–513. [CrossRef].[PubMed].
    [Google Scholar]
  19. Heath W. R. , Carbone F. R. . ( 2001; ). Cross-presentation in viral immunity and self-tolerance. . Nat Rev Immunol 1:, 126–134. [CrossRef].[PubMed].
    [Google Scholar]
  20. Hengel H. , Reusch U. , Geginat G. , Holtappels R. , Ruppert T. , Hellebrand E. , Koszinowski U. H. . ( 2000; ). Macrophages escape inhibition of major histocompatibility complex class I-dependent antigen presentation by cytomegalovirus. . J Virol 74:, 7861–7868. [CrossRef].[PubMed].
    [Google Scholar]
  21. Holtappels R. , Podlech J. , Geginat G. , Steffens H.-P. , Thomas D. , Reddehase M. J. . ( 1998; ). Control of murine cytomegalovirus in the lungs: relative but not absolute immunodominance of the immediate-early 1 nonapeptide during the antiviral cytolytic T-lymphocyte response in pulmonary infiltrates. . J Virol 72:, 7201–7212.[PubMed].
    [Google Scholar]
  22. Holtappels R. , Pahl-Seibert M. F. , Thomas D. , Reddehase M. J. . ( 2000; ). Enrichment of immediate-early 1 (m123/pp89) peptide-specific CD8 T cells in a pulmonary CD62L(lo) memory-effector cell pool during latent murine cytomegalovirus infection of the lungs. . J Virol 74:, 11495–11503. [CrossRef].[PubMed].
    [Google Scholar]
  23. Holtappels R. , Grzimek N. K. A. , Simon C. O. , Thomas D. , Dreis D. , Reddehase M. J. . ( 2002a; ). Processing and presentation of murine cytomegalovirus pORFm164-derived peptide in fibroblasts in the face of all viral immunosubversive early gene functions. . J Virol 76:, 6044–6053. [CrossRef].[PubMed].
    [Google Scholar]
  24. Holtappels R. , Thomas D. , Podlech J. , Reddehase M. J. . ( 2002b; ). Two antigenic peptides from genes m123 and m164 of murine cytomegalovirus quantitatively dominate CD8 T-cell memory in the H-2d haplotype. . J Virol 76:, 151–164. [CrossRef].[PubMed].
    [Google Scholar]
  25. Holtappels R. , Gillert-Marien D. , Thomas D. , Podlech J. , Deegen P. , Herter S. , Oehrlein-Karpi S. A. , Strand D. , Wagner M. , Reddehase M. J. . ( 2006; ). Cytomegalovirus encodes a positive regulator of antigen presentation. . J Virol 80:, 7613–7624. [CrossRef].[PubMed].
    [Google Scholar]
  26. Holtappels R. , Böhm V. , Podlech J. , Reddehase M. J. . ( 2008a; ). CD8 T-cell-based immunotherapy of cytomegalovirus infection: “proof of concept” provided by the murine model. . Med Microbiol Immunol (Berl) 197:, 125–134. [CrossRef].[PubMed].
    [Google Scholar]
  27. Holtappels R. , Simon C. O. , Munks M. W. , Thomas D. , Deegen P. , Kühnapfel B. , Däubner T. , Emde S. F. , Podlech J. et al. ( 2008b; ). Subdominant CD8 T-cell epitopes account for protection against cytomegalovirus independent of immunodomination. . J Virol 82:, 5781–5796. [CrossRef].[PubMed].
    [Google Scholar]
  28. Holtappels R. , Thomas D. , Reddehase M. J. . ( 2009; ). The efficacy of antigen processing is critical for protection against cytomegalovirus disease in the presence of viral immune evasion proteins. . J Virol 83:, 9611–9615. [CrossRef].[PubMed].
    [Google Scholar]
  29. Hutchinson S. , Sims S. , O’Hara G. , Silk J. , Gileadi U. , Cerundolo V. , Klenerman P. . ( 2011; ). A dominant role for the immunoproteasome in CD8+ T cell responses to murine cytomegalovirus. . PLoS ONE 6:, e14646. [CrossRef].[PubMed].
    [Google Scholar]
  30. Jung S. , Aliberti J. , Graemmel P. , Sunshine M. J. , Kreutzberg G. W. , Sher A. , Littman D. R. . ( 2000; ). Analysis of fractalkine receptor CX3CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. . Mol Cell Biol 20:, 4106–4114. [CrossRef].[PubMed].
    [Google Scholar]
  31. Karrer U. , Sierro S. , Wagner M. , Oxenius A. , Hengel H. , Koszinowski U. H. , Phillips R. E. , Klenerman P. . ( 2003; ). Memory inflation: continuous accumulation of antiviral CD8+ T cells over time. . J Immunol 170:, 2022–2029.[PubMed].[CrossRef]
    [Google Scholar]
  32. Karrer U. , Wagner M. , Sierro S. , Oxenius A. , Hengel H. , Dumrese T. , Freigang S. , Koszinowski U. H. , Phillips R. E. , Klenerman P. . ( 2004; ). Expansion of protective CD8+ T-cell responses driven by recombinant cytomegaloviruses. . J Virol 78:, 2255–2264. [CrossRef].[PubMed].
    [Google Scholar]
  33. Klein L. , Hinterberger M. , Wirnsberger G. , Kyewski B. . ( 2009; ). Antigen presentation in the thymus for positive selection and central tolerance induction. . Nat Rev Immunol 9:, 833–844. [CrossRef].[PubMed].
    [Google Scholar]
  34. Klenerman P. , Dunbar P. R. . ( 2008; ). CMV and the art of memory maintenance. . Immunity 29:, 520–522. [CrossRef].[PubMed].
    [Google Scholar]
  35. Kurts C. , Robinson B. W. , Knolle P. A. . ( 2010; ). Cross-priming in health and disease. . Nat Rev Immunol 10:, 403–414. [CrossRef].[PubMed].
    [Google Scholar]
  36. Kurz S. K. , Steffens H.-P. , Mayer A. , Harris J. R. , Reddehase M. J. . ( 1997; ). Latency versus persistence or intermittent recurrences: evidence for a latent state of murine cytomegalovirus in the lungs. . J Virol 71:, 2980–2987.[PubMed].
    [Google Scholar]
  37. Kurz S. K. , Rapp M. , Steffens H.-P. , Grzimek N. K. A. , Schmalz S. , Reddehase M. J. . ( 1999; ). Focal transcriptional activity of murine cytomegalovirus during latency in the lungs. . J Virol 73:, 482–494.[PubMed].
    [Google Scholar]
  38. Lemmermann N. A. , Podlech J. , Seckert C. K. , Kropp K. A. , Grzimek N. K. , Reddehase M. J. , Holtappels R. . ( 2010; ). CD8 T-cell immunotherapy of cytomegalovirus disease in the murine model. . In Methods in Microbiology, Immunology of Infection, vol. 37, , 3rd edn., pp. 369–420. Edited by Kabelitz D. , Kaufmann S. H. E. . . London:: Academic Press;. [CrossRef].
    [Google Scholar]
  39. Lemmermann N. A. , Böhm V. , Holtappels R. , Reddehase M. J. . ( 2011a; ). In vivo impact of cytomegalovirus evasion of CD8 T-cell immunity: Facts and thoughts based on murine models. . Virus Res 157:, 161–174. [CrossRef].[PubMed].
    [Google Scholar]
  40. Lemmermann N. A. , Kropp K. A. , Seckert C. K. , Grzimek N. K. , Reddehase M. J. . ( 2011b; ). Reverse genetics modification of cytomegalovirus antigenicity and immunogenicity by CD8 T-cell epitope deletion and insertion. . J Biomed Biotechnol 2011:, 812742. [CrossRef].[PubMed].
    [Google Scholar]
  41. Marquardt A. , Halle S. , Seckert C. K. , Lemmermann N. A. , Veres T. Z. , Braun A. , Maus U. A. , Förster R. , Reddehase M. J. et al. ( 2011; ). Single cell detection of latent cytomegalovirus reactivation in host tissue. . J Gen Virol 92:, 1279–1291. [CrossRef].[PubMed].
    [Google Scholar]
  42. Mercer J. A. , Wiley C. A. , Spector D. H. . ( 1988; ). Pathogenesis of murine cytomegalovirus infection: identification of infected cells in the spleen during acute and latent infections. . J Virol 62:, 987–997.[PubMed].
    [Google Scholar]
  43. Munks M. W. , Cho K. S. , Pinto A. K. , Sierro S. , Klenerman P. , Hill A. B. . ( 2006a; ). Four distinct patterns of memory CD8 T cell responses to chronic murine cytomegalovirus infection. . J Immunol 177:, 450–458.[PubMed].[CrossRef]
    [Google Scholar]
  44. Munks M. W. , Gold M. C. , Zajac A. L. , Doom C. M. , Morello C. S. , Spector D. H. , Hill A. B. . ( 2006b; ). Genome-wide analysis reveals a highly diverse CD8 T cell response to murine cytomegalovirus. . J Immunol 176:, 3760–3766.[PubMed].[CrossRef]
    [Google Scholar]
  45. Munks M. W. , Pinto A. K. , Doom C. M. , Hill A. B. . ( 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.[PubMed].[CrossRef]
    [Google Scholar]
  46. Pahl-Seibert M. F. , Juelch M. , Podlech J. , Thomas D. , Deegen P. , Reddehase M. J. , Holtappels R. . ( 2005; ). Highly protective in vivo function of cytomegalovirus IE1 epitope-specific memory CD8 T cells purified by T-cell receptor-based cell sorting. . J Virol 79:, 5400–5413. [CrossRef].[PubMed].
    [Google Scholar]
  47. Podlech J. , Holtappels R. , Wirtz N. , Steffens H.-P. , Reddehase M. J. . ( 1998; ). Reconstitution of CD8 T cells is essential for the prevention of multiple-organ cytomegalovirus histopathology after bone marrow transplantation. . J Gen Virol 79:, 2099–2104.[PubMed].
    [Google Scholar]
  48. Podlech J. , Holtappels R. , Pahl-Seibert M.-F. , Steffens H.-P. , Reddehase M. J. . ( 2000; ). Murine model of interstitial cytomegalovirus pneumonia in syngeneic bone marrow transplantation: persistence of protective pulmonary CD8-T-cell infiltrates after clearance of acute infection. . J Virol 74:, 7496–7507. [CrossRef].[PubMed].
    [Google Scholar]
  49. Podlech J. , Holtappels R. , Grzimek N. K. A. , Reddehase M. J. . ( 2002; ). Animal models: murine cytomegalovirus. . Methods in Microbiology 32:, 493–525. [CrossRef]
    [Google Scholar]
  50. Reddehase M. J. . ( 2002; ). Antigens and immunoevasins: opponents in cytomegalovirus immune surveillance. . Nat Rev Immunol 2:, 831–844. [CrossRef].[PubMed].
    [Google Scholar]
  51. Reddehase M. J. , Weiland F. , Münch K. , Jonjic S. , Lüske A. , Koszinowski U. H. . ( 1985; ). Interstitial murine cytomegalovirus pneumonia after irradiation: characterization of cells that limit viral replication during established infection of the lungs. . J Virol 55:, 264–273.[PubMed].
    [Google Scholar]
  52. Reddehase M. J. , Rothbard J. B. , Koszinowski U. H. . ( 1989; ). A pentapeptide as minimal antigenic determinant for MHC class I-restricted T lymphocytes. . Nature 337:, 651–653. [CrossRef].[PubMed].
    [Google Scholar]
  53. Reddehase M. J. , Simon C. O. , Seckert C. K. , Lemmermann N. , Grzimek N. K. . ( 2008; ). Murine model of cytomegalovirus latency and reactivation. . Curr Top Microbiol Immunol 325:, 315–331. [CrossRef].[PubMed].
    [Google Scholar]
  54. Reeves M. , Sinclair J. . ( 2008; ). Aspects of human cytomegalovirus latency and reactivation. . Curr Top Microbiol Immunol 325:, 297–313. [CrossRef].[PubMed].
    [Google Scholar]
  55. Rubocki R. J. , Hansen T. H. , Lee D. R. . ( 1986; ). Molecular studies of murine mutant BALB/c-H-2dm2 define a deletion of several class I genes including the entire H-2Ld gene. . Proc Natl Acad Sci U S A 83:, 9606–9610. [CrossRef].[PubMed].
    [Google Scholar]
  56. Schnorrer P. , Behrens G. M. , Wilson N. S. , Pooley J. L. , Smith C. M. , El-Sukkari D. , Davey G. , Kupresanin F. , Li M. et al. ( 2006; ). The dominant role of CD8+ dendritic cells in cross-presentation is not dictated by antigen capture. . Proc Natl Acad Sci U S A 103:, 10729–10734. [CrossRef].[PubMed].
    [Google Scholar]
  57. Seckert C. K. , Renzaho A. , Reddehase M. J. , Grzimek N. K. . ( 2008; ). Hematopoietic stem cell transplantation with latently infected donors does not transmit virus to immunocompromised recipients in the murine model of cytomegalovirus infection. . Med Microbiol Immunol (Berl) 197:, 251–259. [CrossRef].[PubMed].
    [Google Scholar]
  58. Seckert C. K. , Renzaho A. , Tervo H.-M. , Krause C. , Deegen P. , Kühnapfel B. , Reddehase M. J. , Grzimek N. K. A. . ( 2009; ). Liver sinusoidal endothelial cells are a site of murine cytomegalovirus latency and reactivation. . J Virol 83:, 8869–8884. [CrossRef].[PubMed].
    [Google Scholar]
  59. Shen L. , Rock K. L. . ( 2006; ). Priming of T cells by exogenous antigen cross-presented on MHC class I molecules. . Curr Opin Immunol 18:, 85–91. [CrossRef].[PubMed].
    [Google Scholar]
  60. Simon C. O. , Seckert C. K. , Dreis D. , Reddehase M. J. , Grzimek N. K. A. . ( 2005; ). Role for tumor necrosis factor alpha in murine cytomegalovirus transcriptional reactivation in latently infected lungs. . J Virol 79:, 326–340. [CrossRef].[PubMed].
    [Google Scholar]
  61. Simon C. O. , Holtappels R. , Tervo H.-M. , Böhm V. , Däubner T. , Oehrlein-Karpi S. A. , Kühnapfel B. , Renzaho A. , Strand D. et al. ( 2006; ). CD8 T cells control cytomegalovirus latency by epitope-specific sensing of transcriptional reactivation. . J Virol 80:, 10436–10456. [CrossRef].[PubMed].
    [Google Scholar]
  62. Snyder C. M. , Cho K. S. , Bonnett E. L. , van Dommelen S. , Shellam G. R. , Hill A. B. . ( 2008; ). Memory inflation during chronic viral infection is maintained by continuous production of short-lived, functional T cells. . Immunity 29:, 650–659. [CrossRef].[PubMed].
    [Google Scholar]
  63. Snyder C. M. , Allan J. E. , Bonnett E. L. , Doom C. M. , Hill A. B. . ( 2010; ). Cross-presentation of a spread-defective MCMV is sufficient to prime the majority of virus-specific CD8+ T cells. . PLoS ONE 5:, e9681. [CrossRef].[PubMed].
    [Google Scholar]
  64. Thimme R. , Appay V. , Koschella M. , Panther E. , Roth E. , Hislop A. D. , Rickinson A. B. , Rowland-Jones S. L. , Blum H. E. , Pircher H. . ( 2005; ). Increased expression of the NK cell receptor KLRG1 by virus-specific CD8 T cells during persistent antigen stimulation. . J Virol 79:, 12112–12116. [CrossRef].[PubMed].
    [Google Scholar]
  65. Vermaelen K. , Pauwels R. . ( 2004; ). Accurate and simple discrimination of mouse pulmonary dendritic cell and macrophage populations by flow cytometry: methodology and new insights. . Cytometry 61A:, 170–177. [CrossRef].[PubMed].
    [Google Scholar]
  66. Wiesel M. , Walton S. , Richter K. , Oxenius A. . ( 2009; ). Virus-specific CD8 T cells: activation, differentiation and memory formation. . APMIS 117:, 356–381. [CrossRef].[PubMed].
    [Google Scholar]
  67. Wills M. R. , Carmichael A. J. , Sissons J. G. P. . ( 2006; ). Adaptive cellular immunology to human cytomegalovirus. . In Cytomegaloviruses: Molecular Biology and Immunology, pp. 341–365. Edited by Reddehase M. J. . . Wymondham, UK:: Caister Academic Press;.
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.031815-0
Loading
/content/journal/jgv/10.1099/vir.0.031815-0
Loading

Data & Media loading...

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error