TY - JOUR
T1 - Subdominant CD8 T-cell epitopes account for protection against cytomegalovirus independent of immunodomination
AU - Holtappels, Rafaela
AU - Simon, Christian O.
AU - Munks, Michael W.
AU - Thomas, Doris
AU - Deegen, Petra
AU - Kühnapfel, Birgit
AU - Däubner, Torsten
AU - Emde, Simone F.
AU - Podlech, Jürgen
AU - Grzimek, Natascha K.A.
AU - Oehrlein-Karpi, Silke A.
AU - Hill, Ann B.
AU - Reddehase, Matthias J.
PY - 2008/6
Y1 - 2008/6
N2 - 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-AIDE, 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-ΔIDE and the corresponding revertant virus mCMV-revΔIDE 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.
AB - 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-AIDE, 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-ΔIDE and the corresponding revertant virus mCMV-revΔIDE 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.
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U2 - 10.1128/JVI.00155-08
DO - 10.1128/JVI.00155-08
M3 - Article
C2 - 18367531
AN - SCOPUS:44949213028
SN - 0022-538X
VL - 82
SP - 5781
EP - 5796
JO - Journal of virology
JF - Journal of virology
IS - 12
ER -