Platform-Imprinted Transcriptional and Clonal Remodeling of αβ and γδT Cells After Allogeneic Transplantation

Abstract Immune reconstitution after allogeneic hematopoietic stem cell transplantation is influenced by graft-composition and viral reactivation, but the combined long-term impact on αβ and γδT cells remains unclear. We analyzed a cohort of 213 patients receiving either αβT cell-depleted grafts (n=146; graft engineering that removes donor αβT cells) or T cell-replete grafts (n=67; containing donor T cells). Longitudinal immune phenotyping was integrated with bulk and single-cell TCR repertoire and transcriptomic profiling. CMV reactivation was associated with expansion of CD8 + αβT cells across both transplant types and with numerical dominance of Vδ2 − γδT cells specifically in αβT cell-depleted recipients. Vδ2 − γδT cells underwent early polyclonal expansion followed by repertoire focusing, independent of CMV, whereas αβT cells remained clonally restricted. Reduced early Vδ2 + γδTCR diversity was associated with EBV reactivation. Single-cell and TCR tracking analyses revealed long-term persistence of donor-derived Vδ2 + γδTCRs, whereas Vδ1 + γδ and αβT cell repertoires were predominantly rebuilt de novo. Despite de novo rebuilding, αβTCR repertoire diversity diverged by platform at one year: αβT cell-depleted recipients exhibited marked (hyper)expansion of αβTCR clonotypes and lower diversity than T cell-replete recipients, indicating a durable imprint of graft engineering on αβTCR-clonality. Transcriptomic profiling showed that post-transplant T cells predominantly adopted effector programs, with platform-dependent polarization toward cytotoxic signatures in αβT cell–depleted recipients and toward AREG-associated tissue-repair signatures in T cell–replete recipients, consistent with wound-healing functions. In conclusion, transplantation platforms imprint durable clonal and transcriptional remodeling of αβ and γδT cells, while viral reactivation primarily amplifies expansion without fundamentally reshaping repertoire architecture. Abstract Figure