Protective Immunity Transferred by Infusion of Cytomegalovirus-Specific CD8⁺ T Cells within Donor Grafts: Its Associations with Cytomegalovirus Reactivation Following Unmanipulated Allogeneic Hematopoietic Stem Cell Transplantation

Human cytomegalovirus (CMV)-specific cytotoxic T lymphocyte (CTL) immune response must be reconstituted for long-term protection against CMV relapse and disease in hematopoietic stem cell transplantation (HSCT) recipients. We phenotypically quantitated absolute numbers of CMV-pp65 peptide-specific CTLs (CTL_CMV) in 50 related donor unmanipulated allografts infused into HLA-matched or -mismatched recipients and examined the incidence of CMV reactivation. High CTL_CMV with terminally differentiated effector CD45RO^-CD62L^- cell (T_EMRA) phenotype in the allografts were associated with reduced risk of CMV reactivation, in the presence of sufficient CD45RO⁺CD62L^- cell (T_EM) infusion (≥0.208 × 10⁶/kg). Early after transplantation, there was significant expansion of CTL_CMV with the central memory CD45RO⁺CD62L⁺ cell (T_CM) phenotype when CMV was reactivated. The frequencies of CTL_CMV T_Naive (CD45RO^-CD62L⁺), T_CM, and T_EM at day 90 posttransplantation and of CTL_CMV T_EMRA at day 60 posttransplantation were greater in recipients with higher infusions of CTL_CMV T_EMRA, suggesting protective immunity transferred by infusion of CTL_CMV within allografts. Moreover, the majority of the CTL_CMV identified in the recipients early after HSCT was of donor origin. Our findings support that measuring levels of CTL_CMV and its subsets in the donor grafts and manipulating these cells early after transplantation may help control CMV reactivation, which is closely correlated with immune reconstitution and differentiation of CTL_CMV subsets.

Key Words: Allogeneic hematopoietic stem cell transplantation, CMV reactivation, Antigen-specific CTL, Donor grafts