from Rafaela Holtappels, Stefan Ebert, Jürgen Podlech, Annette Fink, Verena Böhm, Niels A.W. Lemmermann, Kirsten Freitag, Angélique Renzaho, Doris Thomas and Matthias J. Reddehase writing in Cytomegaloviruses: From Molecular Pathogenesis to Intervention:
Cytomegalovirus (CMV) disease is a clinically relevant complication in hematopoietic (stem) cell transplantation (HCT). The murine model of CMV infection in the phase of hematopoietic reconstitution after experimental HCT has been pivotal in defining efficient endogenous reconstitution of donor (D)-derived antiviral CD8+ T cells as the decisive immune parameter for the control of lytic CMV replication and the prevention of acute manifestations of end-organ disease in HCT recipients (R). Endogenous reconstitution of protective immunity occurs with some delay, since hematopoietic stem cells and T-cell lineage lymphopoietic progenitors need to engraft in bone marrow (BM) stroma, migrate to the thymus for thymic self/non self T-cell receptor specificity selection, and emigrate as mature but naïve CD44low T cells to the periphery where they encounter viral antigen to become 'primed', expand clonally, and differentiate into antiviral effector and memory cell subsets. These processes take time, and depending on when CMV reactivates in HCT recipients, endogenous reconstitution may come too late. In addition, the murine model has shown that CMV directly interferes with endogenous reconstitution by infecting BM stromal cells and inhibiting the expression of stromal cell-derived hemopoietins, specifically of stem cell factor (SCF). Depending on the precise conditions, BM pathogenesis of CMV, often referred to as 'myelosuppression', can range from reduced engraftment to a complete graft failure resulting in BM aplasia. Substituting HCT with already primed, 'ready-to-go' CMV-specific CD8+ effector and/or memory T cells, also known as 'adoptive T-cell transfer' or 'preemptive cytoimmunotherapy', can provide immediate protection. Key parameters of protection by CD8+ T cells were revealed by the murine model: (i) memory cell subsets isolated ex vivo from immune donors are ~ 100-fold more efficient than cell culture-propagated short-term cytolytic effector cell lines of identical specificity, (ii) the magnitude of the primary immune response to a viral epitope, its 'immunodominance', does not correlate with protection mediated by cognate T cells; (iii) viral immune evasion proteins determine if an epitope is 'protective', and (iv) genetic deletion of dominant protective epitopes in either the donor's or the recipient's virus has little impact on protection by a broadly-specific T-cell population, predicting 'robustness' of T-cell immunotherapy towards antigenic variation in virus strains or clinical isolates.
Further reading: Cytomegaloviruses: From Molecular Pathogenesis to Intervention