Biology subjects

Stuut, A. H. G.

Publications and source records attributed to Stuut, A. H. G..

2 recordsLinked to original sources

bioRxiv2026

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

immunology↗

bioRxiv2025

Functional γδT-omics pipeline reveals compartmentalization of Vδ1⁺ T cell migration, tumor-reactivity, and clonality in human colorectal cancer

{gamma}{delta}T cells play a pivotal role in cancer immune surveillance, yet the current knowledge of their function across the compartments in solid tumors is meager. To address this gap, we developed a comprehensive {gamma}{delta}T-omics platform that integrates functional screening, biomimetic migration assays, {gamma}{delta}TCR repertoire analysis, and transcriptomic profiling. Using matched samples from 31 patients with microsatellite-stable colorectal cancer (CRC), we analyzed {gamma}{delta}T cells from peripheral blood (PBLs{gamma}{delta}), adjacent colon (LPLs{gamma}{delta}), primary tumors (pTILs{gamma}{delta}), and liver metastases (mTILs{gamma}{delta}). This approach uncovered striking compartmentalization of {gamma}{delta}T cell phenotypes, clonality, and function. Tumor-reactive, clonally expanded V{delta}1 {gamma}{delta}T cells were enriched in primary tumors and shared transcriptional and functional features with lamina propria lymphocytes (LPLs). In contrast, V{delta}1 {gamma}{delta}T cells from liver metastases lacked tumor reactivity, exhibited distinct {gamma}{delta}TCR repertoires, and expressed transcriptional signatures associated with TGF-{beta}-mediated suppression and cellular quiescence, suggesting they are shaped by tissue-specific environmental cues. CXCL16 secretion by tumor cells initiated V{delta}1 LPLs{gamma}{delta} migration, which was further amplified by {gamma}{delta}TCR-mediated CCL5 induction from pTILs{gamma}{delta}, leading to CCR5 downregulation and subsequent entrapment of pTILs{gamma}{delta} within the tumor microenvironment. Accordingly, our clinical data from an independent second cohort of 69 patients showed that infiltration by pTILs{gamma}{delta}, but not mTILs{gamma}{delta}, is associated with a protective effect against CRC progression. In summary, our study offers a compartment-resolved perspective on {gamma}{delta}T cell behavior in CRC, revealing key trafficking and functional mechanisms, and enabling the identification of novel tumor-reactive {gamma}{delta}TCRs and migratory cues to inform immunotherapeutic strategies for both primary and metastatic CRC. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=179 SRC="FIGDIR/small/671055v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@ff3bborg.highwire.dtl.DTLVardef@14a7e1forg.highwire.dtl.DTLVardef@19e4de4org.highwire.dtl.DTLVardef@bc600_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗