title: Subdominant CD8 T-cell epitopes account for protection against cytomegalovirus independent of immunodomination.
abstract: 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-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 murine CMV (mCMV) recombinant virus mCMV-DeltaIDE, 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-DeltaIDE and the corresponding revertant virus mCMV-revDeltaIDE 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.
authors: Institute for Virology, Johannes Gutenberg University, Hochhaus am Augustusplatz, 55131 Mainz, Germany. R.Holtappels-Geginat@uni-mainz.de
authors: Rafaela
authors: R
authors: Holtappels
authors: Christian O
authors: CO
authors: Simon
authors: Michael W
authors: MW
authors: Munks
authors: Doris
authors: D
authors: Thomas
authors: Petra
authors: P
authors: Deegen
authors: Birgit
authors: B
authors: Kühnapfel
authors: Torsten
authors: T
authors: Däubner
authors: Simone F
authors: SF
authors: Emde
authors: Jürgen
authors: J
authors: Podlech
authors: Natascha K A
authors: NK
authors: Grzimek
authors: Silke A
authors: SA
authors: Oehrlein-Karpi
authors: Ann B
authors: AB
authors: Hill
authors: Matthias J
authors: MJ
authors: Reddehase
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D005347:Fibroblasts / Q000821:virology; D006566:Herpesviridae Infections / Q000276:immunology*; D016056:Immunodominant Epitopes / Q000235:genetics; D007700:Kinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D018146:Muromegalovirus / Q000276:immunology*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; D014764:Viral Proteins