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Journal of Virology, June 2008, p. 5781-5796, Vol. 82, No. 12
0022-538X/08/$08.00+0     doi:10.1128/JVI.00155-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Subdominant CD8 T-Cell Epitopes Account for Protection against Cytomegalovirus Independent of Immunodomination{triangledown} ,{dagger}

Rafaela Holtappels,1* Christian O. Simon,1 Michael W. Munks,2,{ddagger} Doris Thomas,1 Petra Deegen,1 Birgit Kühnapfel,1 Torsten Däubner,1 Simone F. Emde,1 Jürgen Podlech,1 Natascha K. A. Grzimek,1 Silke A. Oehrlein-Karpi,1 Ann B. Hill,2 and Matthias J. Reddehase1

Institute for Virology, Johannes Gutenberg University, 55131 Mainz, Germany,1 Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon 972392

Received 22 January 2008/ Accepted 17 March 2008

Cytomegalovirus (CMV) infection continues to be a complication in recipients of hematopoietic stem cell transplantation (HSCT). Preexisting donor immunity is recognized as a favorable prognostic factor for the reconstitution of protective antiviral immunity mediated primarily by CD8 T cells. Furthermore, adoptive transfer of CMV-specific memory CD8 T (CD8-TM) cells is a therapeutic option for preventing CMV disease in HSCT recipients. Given the different CMV infection histories of donor and recipient, a problem may arise from an antigenic mismatch between the CMV variant that has primed donor immunity and the CMV variant acquired by the recipient. Here, we have used the BALB/c mouse model of CMV infection in the immunocompromised host to evaluate the importance of donor-recipient CMV matching in immundominant epitopes (IDEs). For this, we generated the murine CMV (mCMV) recombinant virus mCMV-{Delta}IDE, in which the two memory repertoire IDEs, the IE1-derived peptide 168-YPHFMPTNL-176 presented by the major histocompatibility complex class I (MHC-I) molecule Ld and the m164-derived peptide 257-AGPPRYSRI-265 presented by the MHC-I molecule Dd, are both functionally deleted. Upon adoptive transfer, polyclonal donor CD8-TM cells primed by mCMV-{Delta}IDE and the corresponding revertant virus mCMV-rev{Delta}IDE controlled infection of immunocompromised recipients with comparable efficacy and regardless of whether or not IDEs were presented in the recipients. Importantly, CD8-TM cells primed under conditions of immunodomination by IDEs protected recipients in which IDEs were absent. This shows that protection does not depend on compensatory expansion of non-IDE-specific CD8-TM cells liberated from immunodomination by the deletion of IDEs. We conclude that protection is, rather, based on the collective antiviral potential of non-IDEs independent of the presence or absence of IDE-mediated immunodomination.

* Corresponding author. Mailing address: Institute for Virology, Johannes Gutenberg University, Hochhaus am Augustusplatz, 55131 Mainz, Germany. Phone: 49 6131 39 34451. Fax: 49 6131 39 35604. E-mail: R.Holtappels-Geginat{at}uni-mainz.de

{triangledown} Published ahead of print on 26 March 2008.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

{ddagger} Present address: National Jewish Medical and Research Center, Howard Hughes Medical Institute, 1400 Jackson St., K512, Denver, CO 80206.

Journal of Virology, June 2008, p. 5781-5796, Vol. 82, No. 12
0022-538X/08/$08.00+0     doi:10.1128/JVI.00155-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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