Late diversification in the clonal composition of human cytomegalovirus-specific CD8+ T cells following allogeneic hemopoietic stem cell transplantation

• Published in: Blood Vol. 102; no. 9; pp. 3427 - 3438
• Main Authors: Gandhi, Maher K., Wills, Mark R., Okecha, Georgina, Day, Elizabeth K., Hicks, Ray, Marcus, Robert E., Sissons, J. G. Patrick, Carmichael, Andrew J.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 01-11-2003; The Americain Society of Hematology
• Subjects: Adult; Anemia, Refractory, with Excess of Blasts - therapy; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Antigens, Viral - physiology; Biological and medical sciences; Bone marrow, stem cells transplantation. Graft versus host reaction; CD8-Positive T-Lymphocytes - immunology; Clone Cells - immunology; Cytomegalovirus - immunology; Female; Graft Survival; Hematopoietic Stem Cell Transplantation - methods; Herpesvirus 4, Human - immunology; Humans; Leukemia - therapy; Lymphocyte Activation - immunology; Male; Medical sciences; Middle Aged; Prospective Studies; Tissue Donors; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Transplantation Chimera; Transplantation, Homologous - immunology; Treatment Outcome; Human; Clonality; Herpesviridae; Stem cell; Hematopoietic cell; Homograft; Immune reconstitution; Recipient; Betaherpesvirinae; Human cytomegalovirus; Virus; Specificity; Donor; T-Lymphocyte; Graft
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2002-12-3689

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.