Spatiotemporal Single-Cell Analysis Reveals T Cell Clonal Dynamics and Phenotypic Plasticity in Human Graft-versus-Host Disease
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Allogeneic hematopoietic cell transplantation (alloHCT) is curative for various hematologic diseases but often leads to acute graft-versus-host disease (GVHD), a potentially life-threatening complication. We leverage GVHD as a uniquely tractable disease model to dissect complex T-cell–mediated pathology in 27 alloHCT recipients. We integrate pre-transplant identification of alloreactive T-cells with longitudinal tracking across blood and gut, using mixed lymphocyte reaction-based clonal “fingerprinting”, TCR clonotyping, single-cell RNA/TCR sequencing, and spatial transcriptomics. Using DecompTCR, a novel computational tool for longitudinal TCR analysis, we uncover clonal expansion programs linked to GVHD severity and TCR features. Multi-omics profiling of gut biopsies reveals enrichment and clonal expansion of CD8⁺ effector and ZNF683(Hobit)⁺ resident memory T-cells, cytolytic remodeling of regulatory and unconventional T-cells, and localization of CD8⁺ effector T-cells near intestinal stem cells in crypt loss regions. This framework defines dynamic immune circuit rewiring and phenotypic plasticity with implications for biomarkers and therapies.
Graphical Abstract
Highlights
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Persistent expansion of diverse alloreactive T cell clones is a hallmark of severe GVHD
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DecompTCR reveals dynamic clonal expansion programs linked to GVHD severity and clinical outcome
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CD8+ T cell clones exhibit phenotypic plasticity in vivo across intestinal tissue compartments in GVHD
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High-resolution spatial profiling shows CD8+ effector T cells localize near intestinal stem cell niches and drive epithelial injury in GVHD
