Memory T Cells Specific for Murine Cytomegalovirus Re-Emerge after Multiple Challenges and Recapitulate Immunity in Various Adoptive Transfer Scenarios

Reconstitution of CMV-specific immunity after transplant remains a primary clinical objective to prevent CMV disease, and adoptive immunotherapy of CMV-specific T cells can be an effective therapeutic approach. Because of viral persistence, most CMV-specific CD8(+) T cells become terminally differentiated effector phenotype CD8(+) T cells (T-EFF). A minor subset retains a memorylike phenotype (memory phenotype CD8(+) T cells [T-M]), but it is unknown whether these cells retain memory function or persist over time. Interestingly, recent studies suggest that CMV-specific CD8(+) T cells with different phenotypes have different abilities to reconstitute sustained immunity after transfer. The immunology of human CMV infections is reflected in the murine CMV (MCMV) model. We found that human CMV-and MCMV-specific T cells displayed shared genetic programs, validating the MCMV model for studies of CMV-specific T cells in vivo. The MCMV-specific T-M population was stable over time and retained a proliferative capacity that was vastly superior to T-EFF. Strikingly, after transfer, T-M established sustained and diverse T cell populations even after multiple challenges. Although both T-EFF and T-M could protect Rag(-/)-mice, only T-M persisted after transfer into immune replete, latently infected recipients and responded if recipient immunity was lost. Interestingly, transferred T-M did not expand until recipient immunity was lost, supporting that competition limits the Ag stimulation of T-M. Ultimately, these data show that CMV-specific T-M retain memory function during MCMV infection and can re-establish CMV immunity when necessary. Thus, T-M may be a critical component for consistent, long-term adoptive immunotherapy success.