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bioRxiv · 10.64898/2026.02.09.704768

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

Stuut, A. H. G.·Brazda, P.·Janssen, A.·Vyborova, A.·Karaiskaki, F.·Keramati, F.·de Bont, D. A.·Nicolasen, M. J. T.·Gatti, L.·Hutten, T. J. A.·Yildiz, J.·Spierings, E. T.·Straetemans, T. C. M.·Beringer, D.·Pagliuca, S.·Stunnenberg, H. G.·Sebestyen, Z.·Drylewicz, J.·de Witte, M. A.·Kuball, J. H. E.
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Abstract

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

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Stuut, A. H. G., Brazda, P., Janssen, A., Vyborova, A., Karaiskaki, F., Keramati, F., de Bont, D. A., Nicolasen, M. J. T., Gatti, L., Hutten, T. J. A., Yildiz, J., Spierings, E. T., Straetemans, T. C. M., Beringer, D., Pagliuca, S., Stunnenberg, H. G., Sebestyen, Z., Drylewicz, J., de Witte, M. A., Kuball, J. H. E.. 2026-02-10. Platform-Imprinted Transcriptional and Clonal Remodeling of αβ and γδT Cells After Allogeneic Transplantation. https://doi.org/10.64898/2026.02.09.704768

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