NK- and T-cell repertoire is established early after allogeneic HSCT and is imprinted by CMV reactivation

• Published in: Blood advances 2024-11, Vol.8 (21), p.5612-5624
• Main Authors: Schäfer, Antonia, Calderin Sollet, Zuleika, Hervé, Marie-Priscille, Buhler, Stéphane, Ferrari-Lacraz, Sylvie, Norman, Paul J., Kichula, Katherine M., Farias, Ticiana D. J., Masouridi-Levrat, Stavroula, Mamez, Anne-Claire, Pradier, Amandine, Simonetta, Federico, Chalandon, Yves, Villard, Jean
• Format: Article
• Language: English
• Subjects: Adult; Aged; Cytomegalovirus - immunology; Cytomegalovirus Infections - immunology; Female; Hematopoietic Stem Cell Transplantation - adverse effects; Humans; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Male; Middle Aged; Receptors, Antigen, T-Cell - metabolism; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Transplantation; Transplantation, Homologous; Virus Activation - immunology; Young Adult
• ISSN: 2473-9529; 2473-9537; 2473-9537
• DOI: 10.1182/bloodadvances.2024013117

•The TCR and NK-cell repertoire establish within the first 90 days after transplantation.•CMV reactivation is associated with enhanced TCR clonality and a shift toward enhanced maturation and functionality of NK cells. [Display omitted] Besides genetic influences, nongenetic factors such as graft-versus-host disease and viral infections have been shown to be important shapers of the immune reconstitution and diversification processes after hematopoietic stem cell transplantation (HSCT). However, differential susceptibility to immune modulation by nongenetic factors is not fully understood. We determined to follow the reconstitution of the T-cell receptor (TCR) repertoire through immune sequencing of natural killer (NK) cells using a 35-marker spectral flow cytometry panel and in relation to clinical events. A longitudinal investigation was performed on samples derived from 54 HSCT recipients during the first year after HSCT. We confirmed a significant contraction in TCR repertoire diversity, with remarkable stability over time. Cytomegalovirus (CMV) reactivation had the ability to significantly change TCR repertoire clonality and composition, with a long-lasting imprint. Our data further revealed skewing of NK-cell reconstitution in CMV reactivated recipients, with an increased frequency of KIR2DL2L3S2+ adaptive, cytolytic, and functional CD107a+ NK cells, concomitant with a reduced pool of NKG2A+ NK cells. We provided support that CMV might act as an important driver of peripheral homeostatic proliferation of circulating specific T and NK cells, which can be viewed as a compensatory mechanism to establish a new peripheral repertoire.