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Immune control in the absence of immunodominant epitopes: implications for immunotherapy of cytomegalovirus infection with antiviral CD8 T cells

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Abstract

Adoptive transfer of virus-specific donor-derived CD8 T cells is a therapeutic option to prevent cytomegalovirus (CMV) disease in recipients of hematopoietic cell transplantation. Due to their high coding capacity, human as well as animal CMVs have the potential to encode numerous CD8 T cell epitopes. Although the CD8 T cell response to CMVs is indeed broadly specific in that it involves epitopes derived from almost every open reading frame when tested for cohorts of immune CMV carriers representing the polymorphic MHC/HLA distribution in the population, the response in any one individual is directed against relatively few epitopes selected by the private combination of MHC/HLA alleles. Of this individually selected set of epitopes, few epitopes are ‘immunodominant’ in terms of magnitude of the response directed against them, while others are ‘subdominant’ according to this definition. In the assumption that ‘immunodominance’ indicates ‘relevance’ in antiviral control, research interest was focused on the immunodominant epitopes (IDEs) and their potential use in immunotherapy and in vaccines. The murine model has provided ‘proof of concept’ for the efficacy of CD8 T cell therapy of CMV infection. By experimental modulation of the CD8 T cell ‘immunome’ of murine CMV constructing an IDE deletion mutant, we have used this established cytoimmunotherapy model (a) for evaluating the actual contribution of IDEs to the control of infection and (b) for answering the question whether antigenicity-determining codon polymorphisms in IDE-encoding genes of CMV strains impact on the efficacy of CD8 T cell immunotherapy in case the donor and the recipient harbor different CMV strains.

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Acknowledgments

This work was supported by the Deutsche Forschungsgemeinschaft, SFB 490, and represents a cooperation between individual projects E3 ‘Persistence of murine cytomegalovirus after modulation of the CD8 T cell immunome’ (S.E., D.T., and R.H.) and E2 ‘Immunological control of latent cytomegalovirus infection’ (N.A.W.L., A.R., and M.J.R.). N.A.W.L. and M.J.R. were also supported by the Deutsche Forschungsgemeinschaft, Clinical Research Group KFO 183, individual project TP8 ‘Establishment of challenge models for optimizing the immunotherapy of cytomegalovirus disease,’ and N.A.W.L. received intramural funding in the young investigator program MAIFOR of the University Medical Center of the Johannes Gutenberg-University, Mainz.

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  1. Institute for Virology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Strasse 67, Hochhaus am Augustusplatz, 55131, Mainz, Germany

    Stefan Ebert, Niels A. W. Lemmermann, Doris Thomas, Angélique Renzaho, Matthias J. Reddehase & Rafaela Holtappels

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  1. Stefan Ebert
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  2. Niels A. W. Lemmermann
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  3. Doris Thomas
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  4. Angélique Renzaho
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  5. Matthias J. Reddehase
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  6. Rafaela Holtappels
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Correspondence to Matthias J. Reddehase or Rafaela Holtappels.

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Stefan Ebert and Niels A. W. Lemmermann contributed equally.

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Ebert, S., Lemmermann, N.A.W., Thomas, D. et al. Immune control in the absence of immunodominant epitopes: implications for immunotherapy of cytomegalovirus infection with antiviral CD8 T cells. Med Microbiol Immunol 201, 541–550 (2012). https://doi.org/10.1007/s00430-012-0268-8

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