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

Immune reconstitution after allogeneic hematopoietic stem cell transplantation is influenced by graft-composition and viral reactivation, but the combined long-term impact on {beta} and {gamma}{delta}T cells remains unclear. We analyzed a cohort of 213 patients receiving either {beta}T cell-depleted grafts (n=146; graft engineering that removes donor {beta}T 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+ {beta}T cells across both transplant types and with numerical dominance of V{delta}2- {gamma}{delta}T cells specifically in {beta}T cell-depleted recipients. V{delta}2- {gamma}{delta}T cells underwent early polyclonal expansion followed by repertoire focusing, independent of CMV, whereas {beta}T cells remained clonally restricted. Reduced early V{delta}2+ {gamma}{delta}TCR diversity was associated with EBV reactivation. Single-cell and TCR tracking analyses revealed long-term persistence of donor-derived V{delta}2+ {gamma}{delta}TCRs, whereas V{delta}1+ {gamma}{delta} and {beta}T cell repertoires were predominantly rebuilt de novo. Despite de novo rebuilding, {beta}TCR repertoire diversity diverged by platform at one year: {beta}T cell-depleted recipients exhibited marked (hyper)expansion of {beta}TCR clonotypes and lower diversity than T cell-replete recipients, indicating a durable imprint of graft engineering on {beta}TCR-clonality. Transcriptomic profiling showed that post-transplant T cells predominantly adopted effector programs, with platform-dependent polarization toward cytotoxic signatures in {beta}T 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 {beta} and {gamma}{delta}T cells, while viral reactivation primarily amplifies expansion without fundamentally reshaping repertoire architecture. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/704768v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@88f136org.highwire.dtl.DTLVardef@944f13org.highwire.dtl.DTLVardef@d3835corg.highwire.dtl.DTLVardef@5548ef_HPS_FORMAT_FIGEXP M_FIG C_FIG