title: Late diversification in the clonal composition of human cytomegalovirus-specific CD8+ T cells following allogeneic hemopoietic stem cell transplantation.
abstract: To investigate the mechanisms of human T-cell reconstitution following allogeneic hemopoietic stem cell transplantation (alloSCT), we analyzed the clonal composition of human cytomegalovirus (HCMV)-specific or Epstein-Barr virus (EBV)-specific CD8+ T cells in 10 alloSC transplant recipients and their donors. All virus-specific CD8+ T-cell clones isolated from recipients after alloSCT contained DNA of donor origin. In all 6 D+/R+ sibling alloSCTs from seropositive donors into seropositive recipients, donor virus-specific clones transferred in the allograft underwent early expansion and were maintained long term in the recipient. In contrast, in 2 of 3 HCMV D+/R- alloSC transplant recipients in whom there was no detectable HCMV infection, donor HCMV-specific clones were undetectable, whereas donor EBV-specific clones were maintained in the same EBV-seropositive recipients, suggesting that transferred clones require antigen for their maintenance. Following D-/R+ transplantation from 3 seronegative donors into seropositive recipients, a delayed primary virus-specific CD8+ T-cell response was observed, in which the T cells contained donor DNA, suggesting that new antigen-specific T cells arose in the recipient from donor-derived progenitors. In 2 of 4 HCMV D+/R+ sibling allograft recipients the clonal composition underwent diversification as compared with their donors, with delayed persistent expansion of HCMV-specific clones that were undetectable in the donor or in the recipient during the early months after transplantation; this diversification may represent expansion of new clones generated from donor-derived progenitors. We conclude that, following alloSCT, late diversification of the HCMV-specific CD8+ T-cell clonal repertoire can occur in response to persistent viral antigen.
authors.affiliation: Department of Medicine, University of Cambridge Clinical School, Hills Rd, Cambridge, CB2 2QQ, United Kingdom.
authors.forename: Maher K
authors.initials: MK
authors.lastname: Gandhi
authors.forename: Mark R
authors.initials: MR
authors.lastname: Wills
authors.forename: Georgina
authors.initials: G
authors.lastname: Okecha
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Day
authors.forename: Ray
authors.initials: R
authors.lastname: Hicks
authors.forename: Robert E
authors.initials: RE
authors.lastname: Marcus
authors.forename: J G Patrick
authors.initials: JG
authors.lastname: Sissons
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Carmichael
mesh_terms: D000328:Adult; D000754:Anemia, Refractory, with Excess of Blasts / Q000628:therapy; D000956:Antigens, Viral / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002999:Clone Cells / Q000276:immunology; D003587:Cytomegalovirus / Q000276:immunology*; D005260:Female; D006085:Graft Survival; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D004854:Herpesvirus 4, Human / Q000276:immunology; D006801:Humans; D007938:Leukemia / Q000628:therapy; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D014019:Tissue Donors; D018183:Transplantation Chimera; D014184:Transplantation, Homologous / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D000956:Antigens, Viral