Subdominant CD8 T-cell epitopes account for protection against cytomegalovirus independent of immunodomination

被引:71
作者
Holtappels, Rafaela [1 ]
Simon, Christian O. [1 ]
Munks, Michael W. [2 ]
Thomas, Doris [1 ]
Deegen, Petra [1 ]
Kuehnapfel, Birgit [1 ]
Daeubner, Torsten [1 ]
Emde, Simone F. [1 ]
Podlech, Juergen [1 ]
Grzimek, Natascha K. A. [1 ]
Oehrlein-Karpi, Silke A. [1 ]
Hill, Ann B. [2 ]
Reddehase, Matthias J. [1 ]
机构
[1] Johannes Gutenberg Univ Mainz, Inst Virol, D-55131 Mainz, Germany
[2] Oregon Hlth & Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97239 USA
关键词
D O I
10.1128/JVI.00155-08
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Cytomegalovirus (CW) 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-T-M) 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 marine 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 L-d and the m164-derived peptide 257-AGPPRYSRI-265 presented by the MHC-I molecule D-d, are both functionally deleted. Upon adoptive transfer, polyclonal donor CD8-T-M 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-T-M 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-T-M 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.
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收藏
页码:5781 / 5796
页数:16
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