Skip to main content

Advertisement

SpringerLink
Log in

Epitope-specific in vivo protection against cytomegalovirus disease by CD8 T cells in the murine model of preemptive immunotherapy

  • Original Investigation
  • Published:
Medical Microbiology and Immunology Aims and scope Submit manuscript

Abstract

Preclinical research in murine models as well as subsequent clinical trials have concordantly revealed a high protective potential of antiviral CD8 T cells, of donor-derived ex vivo memory CD8 T cells in particular, in the immunotherapy of cytomegalovirus (CMV) infection in immunocompromised recipients. Although it is generally held view that the observed beneficial effect of the transferred cells is viral epitope-specific, involving the recognition of MHC class-I presented peptides by cognate T cell receptors, this assumption awaits formal proof, at least with regard to the in vivo function of the CD8 T cells. This question is particularly evident for CMV, since the function of viral immune evasion proteins interferes with the MHC class-I pathway of peptide presentation. Alternatively, therefore, one has to consider the possibility that the requirement for epitope recognition may be bypassed by other ligand–receptor interactions between CD8 T cells and infected cells, which may trigger the signaling for effector functions. Clearly, such a mechanism might explain why CD8 T cells are so efficient in controlling CMV infection despite the expression of viral immune evasion proteins. Here we provide direct evidence for epitope-specificity of antiviral protection by employing a recombinant murine CMV (mCMV), namely the mutant virus mCMV-IE1-L176A, in which an immunodominant viral epitope of the regulatory immediate-early protein IE1 is functionally deleted by a point mutation replacing leucine with alanine at the C-terminal MHC anchor position of the antigenic peptide.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Pahl-Seibert MF, Jülch M, Podlech J, Thomas D, Deegen P, Reddehase MJ, 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Steffens HP, Kurz S, Holtappels R, Reddehase MJ (1998) Preemptive CD8 T-cell immunotherapy of acute cytomegalovirus infection prevents lethal disease, limits the burden of latent viral genomes, and reduces the risk of virus recurrence. J Virol 72:1797–1804

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Riddell SR, Watanabe KS, Goodrich JM, Li CR, Agha ME, Greenberg PD (1992) Restoration of viral immunity in immunodeficient humans by the adoptive transfer of T cell clones. Science 257:238–241

    Article  CAS  PubMed  Google Scholar 

  4. Cobbold M, Khan N, Pourgheysari B, Tauro S, McDonald C, Osman H, Assenmacher M, Billingham L, Steward C, Crawley C, Olavarria E, Goldman J, Chakraverty R, Mahendra P, Craddock C, Moss PA (2005) Adoptive transfer of cytomegalovirus-specific CTL to stem cell transplant patients after selection by HLA-peptide tetramers. J Exp Med 202:379–386

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Reddehase MJ (2002) Antigens and immunoevasins: opponents in cytomegalovirus immune surveillance. Nat Rev Immunol 2:831–844

    Article  CAS  PubMed  Google Scholar 

  6. Pinto AK, Munks MW, Koszinowski UH, Hill AB (2006) Coordinated function of murine cytomegalovirus genes completely inhibits CTL lysis. J Immunol 177:3225–3234

    Article  CAS  PubMed  Google Scholar 

  7. Holtappels R, Gillert-Marien D, Thomas D, Podlech J, Deegen P, Herter S, Oehrlein-Karpi SA, Strand D, Wagner M, Reddehase MJ (2006) Cytomegalovirus encodes a positive regulator of antigen presentation. J Virol 80:7613–7624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Holtappels R, Grzimek NK, Simon CO, Thomas D, Dreis D, Reddehase MJ (2002) 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Gold MC, Munks MW, Wagner M, McMahon CW, Kelly A, Kavanagh DG, Slifka MK, Koszinowski UH, Raulet DH, Hill AB (2004) Murine cytomegalovirus interference with antigen presentation has little effect on the size or the effector memory phenotype of the CD8 T cell response. J Immunol 172:6944–6953

    Article  CAS  PubMed  Google Scholar 

  10. Holtappels R, Munks WM, Podlech J, Reddehase MJ (2006) CD8 T-cell-based immunotherapy of cytomegalovirus disease in the mouse model of the immunocompromised bone marrow transplantation recipient. In: Reddehase MJ (ed) Cytomegaloviruses: molecular biology and immunology. Caister Academic Press, Norfolk, pp 383–418

    Google Scholar 

  11. Jonjic S, Bubic I, Krmpotic A (2006) Innate immunity to cytomegaloviruses. In: Reddehase MJ (ed) Cytomegaloviruses: molecular biology and immunology. Caister Academic Press, Norfolk, pp 285–320

    Google Scholar 

  12. Reddehase MJ, Keil GM, Koszinowski UH (1984) The cytolytic T lymphocyte response to the murine cytomegalovirus. II. Detection of virus replication stage-specific antigens by separate populations of in vivo active cytolytic T lymphocyte precursors. Eur J Immunol 14:56–61

    Article  CAS  PubMed  Google Scholar 

  13. Streblow DN, Varnum SM, Smith RD, Nelson JA (2006) A proteomics analysis of human cytomegalovirus particles. In: Reddehase MJ (ed) Cytomegaloviruses: molecular biology and immunology. Caister Academic Press, Norfolk, pp 91–110

    Google Scholar 

  14. Shenk T (2006) Human cytomegalovirus genomics. In: Reddehase MJ (ed) Cytomegaloviruses: molecular biology and immunology. Caister Academic Press, Norfolk, pp 49–62

    Google Scholar 

  15. Boehme KW, Compton T (2006) Virus entry and activation of innate immunity. In: Reddehase MJ (ed) Cytomegaloviruses: molecular biology and immunology. Caister Academic Press, Norfolk, pp 111–130

    Google Scholar 

  16. Hengel H, Brune W, Koszinowski UH (1998) Immune evasion by cytomegalovirus—survival strategies of a highly adapted opportunist. Trends Microbiol 6:190–197

    Article  CAS  PubMed  Google Scholar 

  17. Reddehase MJ, Simon CO, Podlech J, Holtappels R (2004) Stalemating a clever opportunist: lessons from murine cytomegalovirus. Hum Immunol 65:446–455

    Article  CAS  PubMed  Google Scholar 

  18. Lodoen M, Ogasawara K, Hamerman JA, Arase H, Houchins JP, Mocarski ES, Lanier LL (2003) NKG2D-mediated natural killer cell protection against cytomegalovirus is impaired by viral gp40 modulation of retinoic acid early inducible 1 gene molecules. J Exp Med 197:1245–1253

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Pinto AK, Jamieson AM, Raulet DH, Hill AB (2007) The role of NKG2D signaling in inhibition of cytotoxic T-lymphocyte lysis by the murine cytomegalovirus immunoevasin m152/gp40. J Virol 81:12564–12571

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Vivier E, Tomasello E, Paul P (2002) Lymphocyte activation via NKG2D: towards a new paradigm in immune recognition? Curr Opin Immunol 14:306–311

    Article  CAS  PubMed  Google Scholar 

  21. Simon CO, Holtappels R, Tervo HM, Böhm V, Däubner T, Oehrlein-Karpi SA, Kühnapfel B, Renzaho A, Strand D, Podlech J, Reddehase MJ, Grzimek NK (2006) CD8 T cells control cytomegalovirus latency by epitope-specific sensing of transcriptional reactivation. J Virol 80:10436–10456

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Simon CO, Seckert CK, Grzimek NK, Reddehase MJ (2006) Murine model of cytomegalovirus latency and reactivation: the silencing/desilencing and immune sensing hypothesis. In: Reddehase MJ (ed) Cytomegaloviruses: molecular biology and immunology. Caister Academic Press, Norfolk, pp 483–500

    Google Scholar 

  23. Hemmer B, Vergelli M, Pinilla C, Houghten R, Martin R (1998) Probing degeneracy in T-cell recognition using peptide combinatorial libraries. Immunol Today 19:163–168

    Article  CAS  PubMed  Google Scholar 

  24. Eisen HN (2001) Specificity and degeneracy in antigen recognition: yin and yang in the immune system. Annu Rev Immunol 19:1–21

    Article  CAS  PubMed  Google Scholar 

  25. Mazza C, Malissen B (2007) What guides MHC-restricted TCR-recognition? Semin Immunol 19:225–235

    Article  CAS  PubMed  Google Scholar 

  26. Cohn M (2008) An in depth analysis of the concept of “polyspecificity” assumed to characterize TCR/BCR recognition. Immunol Res 40:128–147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Reddehase MJ, Koszinowski UH (1991) Redistribution of critical major histocompatibility complex and T cell receptor-binding functions of residues in an antigenic sequence after biterminal substitution. Eur J Immunol 21:1697–1701

    Article  CAS  PubMed  Google Scholar 

  28. Hokeness KL, Deweerd ES, Munks MW, Lewis CA, Gladue RP, Salazar-Mather TP (2007) CXCR3-dependent recruitment of antigen-specific T-lymphocytes to the liver during murine cytomegalovirus infection. J Virol 81:1241–1250

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We greatly appreciated the help by Markus Jülch (Tumor Vaccination Centre at the III. Medical Clinic, University Clinic Mainz) for help with the cell sorting. This work was supported by the Deutsche Forschungsgemeinschaft, SFB 490, individual projects E2 (N.K.A.G. and M.J.R.), E3 (R.H., D.T., P.D., M-F.P-S.), and E4 (V.B., S.A.O-K., and M.J.R.); SFB 432, individual project A10 (J.P.) and clinical research group KFO 183 (N.A.W.L. and M.J.R.). Special thanks go to the “Dr. Gerhard und Martha Röttger-Stiftung” for a generous donation.

Author information

Authors and Affiliations

  1. Institute for Virology, Johannes Gutenberg-University, Obere Zahlbacher Strasse 67, Hochhaus am Augustusplatz, 55131, Mainz, Germany

    Verena Böhm, Jürgen Podlech, Doris Thomas, Petra Deegen, Marcus-Folker Pahl-Seibert, Niels A. W. Lemmermann, Natascha K. A. Grzimek, Silke A. Oehrlein-Karpi, Matthias J. Reddehase & Rafaela Holtappels

Authors
  1. Verena Böhm
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jürgen Podlech
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Doris Thomas
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Petra Deegen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marcus-Folker Pahl-Seibert
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Niels A. W. Lemmermann
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Natascha K. A. Grzimek
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Silke A. Oehrlein-Karpi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Matthias J. Reddehase
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Rafaela Holtappels
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rafaela Holtappels.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Böhm, V., Podlech, J., Thomas, D. et al. Epitope-specific in vivo protection against cytomegalovirus disease by CD8 T cells in the murine model of preemptive immunotherapy. Med Microbiol Immunol 197, 135–144 (2008). https://doi.org/10.1007/s00430-008-0092-3

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00430-008-0092-3

Keywords

Search

Navigation