Biology subjects

Wang, X. K.

Publications and source records attributed to Wang, X. K..

3 recordsLinked to original sources

bioRxiv2026

A Donor T-Cell Receptor Structural Signature Determines Alloreactive Potential and Predicts Acute Graft-Versus-Host Disease

Acute graft-versus-host disease (GVHD) remains a lethal barrier to successful allogeneic hematopoietic cell transplantation, yet pre-transplant donor selection entirely ignores hypervariable T-cell receptor (TCR) architecture. Here, by characterizing over 64,000 alloreactive clonotypes, we demonstrate that human alloreactivity is dictated by a constrained, predictable baseline structural signature. Pathogenic, tissue-infiltrating alloreactive T cells exhibit significantly shortened CDR3{beta} regions, altered antigen-facing biophysical features, biased VJ gene usage and extensive inter-donor sharing originating from public anti-pathogen memory reservoirs. These potent clones natively cluster within the high-frequency fraction of the unstimulated baseline donor repertoire. We introduce R50, an assay-independent metric quantifying this clonal dominance, which independently predicted a six-fold increased risk of acute GVHD in a cross-institutional cohort. This scalable in silico platform shifts pre-transplant risk stratification from HLA typing and demographic surrogates to precision immune-receptor modeling.

immunology↗

bioRxiv2025

Conserved Landscape of Chemokine Receptor Co-expression Defines the Functional States of CD8+ T Cells in Melanoma

Cancer immunotherapies, from checkpoint blockade to adoptive cell therapies like tumor-infiltrating lymphocytes (TILs), have revolutionized cancer treatment but are limited by variable efficacy and significant toxicities. A central challenge is identifying ideal T-cell populations that effectively eliminate tumors without causing off-target damage, a distinction not captured by existing biomarkers. We show that co-expression patterns of chemokine receptors (CRs) CXCR3, CCR5, and CXCR6 on CD8+ T cells provide a functional "code" defining subsets with divergent roles in on-target immunity versus off-target inflammation. In mouse and human melanoma, a triple-positive (CXCR3+CCR5+CXCR6+) T-cell subset is essential for tumor control, and its genetic signature correlates with positive clinical response, while a distinct CCR5+CXCR6+ subset drives liver immune-related adverse events (IRAEs). Crucially, this CR code reveals that immunotherapy actively reshapes T-cell trafficking patterns, uncovering profound heterogeneity within conventional populations and distinguishing potent anti-tumor progenitors from cells predisposed to exhaustion or off-target migration. This work establishes CR co-expression as a practical tool, providing a surface marker-based strategy to identify and enrich optimized T cells for adoptive therapies, thereby offering a framework to uncouple efficacy from toxicity. One Sentence SummaryCo-expression of CCR5, CXCR6, and CXCR3 provides a functional code that separates T-cell-mediated anti-tumor efficacy from off-target toxicity, enabling the selection of superior cells for safer and more effective cancer immunotherapies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/693486v2_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@19b0f44org.highwire.dtl.DTLVardef@1076129org.highwire.dtl.DTLVardef@17c0be6org.highwire.dtl.DTLVardef@f14893_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LI{middle dot} CXCR6, CXCR3 and CCR5 co-expression signature stratifies patient survival in human melanoma C_LIO_LI{middle dot} CD8+ T cells co-expressing CXCR6, CXCR3 and CCR5 are critical effectors with high proliferative, cytotoxic, and activation profile in human and mice melanoma C_LIO_LI{middle dot} CD8+ T cells co-expressing CXCR6, CXCR3 and CCR5 drive anti-tumoral responses during checkpoint blockade in both human and mice C_LI

immunology↗

bioRxiv2025

Spatiotemporal Single-Cell Analysis Reveals T Cell Clonal Dynamics and Phenotypic Plasticity in Human Graft-versus-Host Disease

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 O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=198 SRC="FIGDIR/small/655962v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@178b77dorg.highwire.dtl.DTLVardef@569226org.highwire.dtl.DTLVardef@1951281org.highwire.dtl.DTLVardef@1f1e046_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIPersistent expansion of diverse alloreactive T cell clones is a hallmark of severe GVHD C_LIO_LIDecompTCR reveals dynamic clonal expansion programs linked to GVHD severity and clinical outcome C_LIO_LICD8+ T cell clones exhibit phenotypic plasticity in vivo across intestinal tissue compartments in GVHD C_LIO_LIHigh-resolution spatial profiling shows CD8+ effector T cells localize near intestinal stem cell niches and drive epithelial injury in GVHD C_LI

systems biology↗