Positive Role of the MHC Class-I Antigen Presentation Regulator m04/gp34 of Murine Cytomegalovirus in Antiviral Protection by CD8 T Cells
Murine cytomegalovirus (mCMV) codes for MHC class-I trafficking modulators m04/gp34, m06/gp48, and m152/gp40. By interacting with the MHC class-Iα chain, these proteins disconnect peptide-loaded MHC class-I (pMHC-I) complexes from the constitutive vesicular flow to the cell surface. Based on the assumption that all three inhibit antigen presentation, and thus the recognition of infected cells by CD8 T cells, they were referred to as “immunoevasins.” Improved antigen presentation mediated by m04 in the presence of m152 after infection with deletion mutant mCMV-Δm06W, compared to mCMV-Δm04m06 expressing only m152, led us to propose renaming these molecules “viral regulators of antigen present…
Enhancement of Antigen Presentation by Deletion of Viral Immune Evasion Genes Prevents Lethal Cytomegalovirus Disease in Minor Histocompatibility Antigen-Mismatched Hematopoietic Cell Transplantation
Hematoablative treatment followed by hematopoietic cell transplantation (HCT) for reconstituting the co-ablated immune system is a therapeutic option to cure aggressive forms of hematopoietic malignancies. In cases of family donors or unrelated donors, immunogenetic mismatches in major histocompatibility complex (MHC) and/or minor histocompatibility (minor-H) loci are unavoidable and bear a risk of graft-vs.-host reaction and disease (GvHR/D). Transient immunodeficiency inherent to the HCT protocol favors a productive reactivation of latent cytomegalovirus (CMV) that can result in multiple-organ CMV disease. In addition, there exists evidence from a mouse model of MHC class-I-mismatched GvH…
Therapeutic Vaccination of Hematopoietic Cell Transplantation Recipients Improves Protective CD8 T-Cell Immunotherapy of Cytomegalovirus Infection
Reactivation of latent cytomegalovirus (CMV) endangers the therapeutic success of hematopoietic cell transplantation (HCT) in tumor patients due to cytopathogenic virus spread that leads to organ manifestations of CMV disease, to interstitial pneumonia in particular. In cases of virus variants that are refractory to standard antiviral pharmacotherapy, immunotherapy by adoptive cell transfer (ACT) of virus-specific CD8+ T cells is the last resort to bridge the “protection gap” between hematoablative conditioning for HCT and endogenous reconstitution of antiviral immunity. We have used the well-established mouse model of CD8+ T-cell immunotherapy by ACT in a setting of experimental HCT and mu…
Revisiting CD8 T-cell ‘Memory Inflation’: New Insights with Implications for Cytomegaloviruses as Vaccine Vectors
Murine models of cytomegalovirus (CMV) infection have revealed an exceptional kinetics of the immune response. After resolution of productive infection, transient contraction of the viral epitope-specific CD8 T-cell pool was found to be followed by a pool expansion specific for certain viral epitopes during non-productive &lsquo