Biology subjects

Xu, C.-J.

Publications and source records attributed to Xu, C.-J..

8 recordsLinked to original sources

bioRxiv2026

Stromal control of sympathetic rewiring in metastatic lymph nodes

Metastatic lymph nodes (LNs) are dynamically remodeled tissues, but this process has been understood mainly in immune and stromal terms. We show that tumor-driven LN remodeling also involves adaptive neural rewiring. In a mouse model of nodal metastasis, sympathetic fibers, but not sensory fibers, progressively expanded during LN remodeling and tracked with metastatic progression. Fibroblastic reticular cells (FRCs) adopted a neuro-supportive program characterized by increased hepatocyte growth factor (HGF) production, while local stromal HGF acted through MET on sympathetic neurons to stimulate neurite outgrowth. Increased substrate stiffness enhanced FRC activation and HGF production, suggesting that mechanical remodeling may reinforce the neuro-supportive stromal state. Inhibition of HGF signaling or ablation of sympathetic innervation reduced LN enlargement and nodal tumor burden. These findings identify neural plasticity as a functional component of the metastatic LN niche and reveal a stromal/mechanical/neural framework that supports metastatic LN progression.

cancer biology↗

bioRxiv2026

Viral persistence and antiretroviral therapy shape systemic immune aging in treated HIV infection

Chronic infections can reshape immune system homeostasis, yet how persistent viral infections influence immune aging remains poorly understood. People living with HIV provide a unique model to investigate how long-term viral persistence affects immune aging despite effective antiretroviral therapy. Here, we characterize immune aging by integrating plasma proteomics with epigenetic and transcriptional profiles of circulating immune cells across large cohorts of treated individuals with HIV. We find that immune aging is markedly accelerated compared with healthy individuals and parallels established DNA methylation-based aging clocks. Accelerated immune aging is strongly associated with signatures of immunosenescence and correlates with the size of the latent HIV reservoir, suggesting a persistent imprint of viral persistence on immune aging trajectories. Notably, exposure to specific antiretroviral agents, particularly nucleoside reverse transcriptase inhibitors, is associated with reduced immune aging and suppression of age-associated immune gene programs. Together, these findings identify chronic viral persistence as a driver of systemic immune aging and indicate that antiretroviral therapy can partially modulate immune aging programs.

immunology↗

bioRxiv2025

A multicenter spatial transcriptomics atlas of human tuberculosis and non-tuberculous mycobacterial disease

Granulomas are the hallmark of mycobacterial (MB) infections, forming structured immune environments that contain bacteria but also drive disease persistence. However, their spatial and functional organization remains unclear. Using spatial RNA sequencing on 38 patient samples, we identified five distinct granuloma niches: a necrotic core, an immune-activated inner niche, an inflammatory and an extracellular matrix (ECM)-remodeling middle niche, an outer structural niche, and a tertiary lymphoid structure niche supporting antigen presentation. Immune activity peaks in the inner niche, transitioning to fibrosis at the periphery. Lymph node granulomas display reduced fibroblast involvement but stronger JAK-STAT activation. Mycobacterium tuberculosis (MTB) granulomas exhibit heightened JAK-STAT and IFN-{gamma} signaling, while non-tuberculous mycobacteria (NTM) granulomas show increased hypoxia signatures. Compared to sarcoidosis, MB granulomas feature a structured adaptive immune response, marked by the clustering of plasma cells. Our findings, accessible via https://lab-li.ciim-hannover.de/mb-granuloma/, define key disease signatures, guiding biomarker discovery and therapeutic targeting in granuloma-related diseases.

bioinformatics↗

bioRxiv2024

Enhancing HBV-specific T cell responses through a combination of epigenetic modulation and immune checkpoint inhibition

ObjectiveChronic hepatitis B virus (HBV) infection results in the exhaustion of HBV-specific T cells and the development of epigenetic imprints that impair immune responses and limit the effectiveness of immune checkpoint inhibitor (ICI) monotherapy, such as PD-L1. This study aimed to determine whether the DNA methyltransferase inhibitor decitabine (DAC) can reverse these epigenetic imprints and enhance the efficacy of ICI in restoring HBV-specific T cell responses. MethodsWe investigated HBV-specific CD4+ and CD8+ T cell responses by 10-day in vitro stimulation of peripheral blood mononuclear cells (PBMCs) from patients with chronic HBV infection. PBMCs were stimulated with HBV core-specific overlapping peptide pools and HLA-A*02-restricted peptides, including core18 and pol455. The immunomodulatory effect of the combination of DAC/PD-L1 was assessed via flow cytometry. Responder stratification was investigated by comparison of clinical characteristics, ex vivo DNA methylation analysis of PBMCs, and determination of IFN{gamma} plasma levels. ResultsTreatment with DAC and PD-L1 enhanced HBV-specific CD4+ T cell responses in a significant proportion of 53 patients, albeit with variability. The effect was independent of the HBcrAg level. Ex vivo DNA methylation revealed hypermethylation of key genes like IFNG among DAC-responders versus non-responders, supported by altered ex vivo IFN{gamma} plasma levels. Further analysis of HBV-specific CD8+ T cell responses in 22 HLA-A*02-positive patients indicated distinct response patterns between HBV-core18- and HBV-pol455-specific T cells, with pol455-specific CD8+ T cells showing increased susceptibility to DAC/PD-L1, surpassing PD-L1 monotherapy response. ConclusionsThe combination of DAC and PD-L1 shows promising effects in improving HBV-specific T cell responses in vitro. Our study highlights the potential of remodeling exhaustion-associated epigenetic signatures to enhance HBV-specific T cell restoration, suggesting a novel immunotherapeutic avenue for chronic HBV infections. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=129 SRC="FIGDIR/small/611632v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@156d0fborg.highwire.dtl.DTLVardef@b22d2corg.highwire.dtl.DTLVardef@1b3c4e2org.highwire.dtl.DTLVardef@1430bbf_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIRemodeling epigenetic signatures with a DNA methyltransferase inhibitor enhances the effectiveness of immune checkpoint inhibition in restoring HBV-specific T cell responses. C_LIO_LIResponsiveness is associated with specific IFN{gamma} DNA methylation patterns and plasma levels. C_LIO_LIEpigenetic remodeling had distinct effects on two CD8 T cell epitopes, with more pronounced effects on HBV-pol455-specific CD8+ T cell responses. C_LI

immunology↗

bioRxiv2024

CellDemux: coherent genetic demultiplexing in single-cell and single-nuclei experiments.

Multiplexed single-cell experiment designs are superior in terms of reduced batch effects, increased cost-effectiveness, throughput and statistical power. However, current computational strategies using genetics to demultiplex single-cell (sc) libraries are limited when applied to single-nuclei (sn) sequencing data (e.g., snATAC-seq and snMultiome). Here, we present CellDemux: a computational framework for genetic demultiplexing within and across data modalities, including single-cell, single-nuclei and paired snMultiome measurements. CellDemux uses a consensus approach, leveraging modality-specific tools to robustly identify non-empty oil droplets and singlets, which are subsequently demultiplexed to donors. Notable, CellDemux demonstrates good performance in demultiplexing snMultiome data and is generalizable to single modalities, i.e. snATAC-seq and sc/snRNA-seq libraries. We benchmark CellDemux on 187 genetically multiplexed libraries from 800 samples (scRNA-seq, snATAC-seq, CITE-seq and snMultiome), confidently identifying and assigning cells to 88% of donors. In paired snMultiome libraries, CellDemux achieves consistent demultiplexing across data modalities. Moreover, analysis of 38 snATAC libraries from 149 samples shows that CellDemux retains more genetically demultiplexed nuclei for downstream analyses compared to existing methods. In summary, CellDemux is a modular and robust framework that deconvolves donors from genetically multiplexed single-cell and single-nuclei RNA/ATAC/Multiome libraries.

genomics↗

bioRxiv2021

Evolution of cytokine production capacity in ancient and modern European populations

As our ancestors migrated throughout the different continents, natural selection increased the presence of alleles advantageous in the new environments. Heritable variations that alter the susceptibility to diseases vary with the historical period, the virulence of the infections, and their geographical spread. In this study we built polygenic scores for heritable traits influencing the genetic adaptation in the production of cytokines and immune-mediated disorders, including infectious, inflammatory, and autoimmune diseases, and applied them to the genomes of several ancient European populations. We observed that the advent of the Neolithic was a turning point for immune-mediated traits in Europeans, favoring those alleles linked with the development of tolerance against intracellular pathogens and promoting inflammatory responses against extracellular microbes. These evolutionary patterns are also associated with an increased presence of traits related to inflammatory and auto-immune diseases.

genomics↗

bioRxiv2020

Cryo-EM structures of inactive and Gi-coupled GABAB heterodimer

Metabotropic GABAB G protein-coupled receptor functions as a mandatory heterodimer of GB1 and GB2 subunits and mediates inhibitory neurotransmission in the central nervous system. Each subunit is composed of the extracellular Venus flytrap (VFT) domain and transmembrane (TM) domain. Here we present cryo-EM structures of human full-length heterodimeric GABAB receptor in the antagonist-bound inactive state and in the active state complexed with agonist and positive allosteric modulator in the presence of Gi1 protein at a resolution range of 2.8-3.0 [A]. Cryo-EM analysis of the activated-GABAB-Gi1 complex revealed that Gi1 couples to the activated receptor primarily in three major conformations, one via GB1 TM and two via GB2 TM, respectively. Our structures reveal that agonist binding stabilizes the closure of GB1 VFT, which in turn triggers a rearrangement of TM interfaces between two subunits from TM3-TM5/TM3-TM5 in the inactive state to TM6/TM6 in the active state and finally induces the opening of intracellular loop 3 and synergistically shifting of TM3, 4 and 5 helices in GB2 TM domain to accommodate the 5-helix of Gi1. These results provide a structural framework for understanding class C GPCR activation and a rational template for allosteric modulator design targeting dimeric interface of GABAB receptor.

molecular biology↗

bioRxiv2019

A key interfacial residue identified with in-cell structure characterization of a Class-A GPCR dimer

G protein coupled receptors (GPCRs) have been shown homo-dimeric. Despite extensive studies, no single residue has been found essential for dimerization. Lacking an efficient method to shift the monomer-dimer equilibrium also makes functional relevance of GPCR dimer elusive. Here, using fluorescence lifetime-based imaging for distance measurements, we characterize the dimeric structure of GPR17, a class A GPCR, in cells. The structure reveals transmembrane helices 5 and 6 the dimer interface, and pinpoints F229 a key residue, mutations of which can render GPR17 monomeric or dimeric. Using the resulting mutants, we show that GPR17 dimer is coupled to both Gi and Gq signaling and is internalized, whereas GPR17 monomer is coupled to Gi signaling only and is not internalized. We further show that residues equivalent to F229 of GPR17 in several other class A GPCRs are also important for dimerization. Our findings thus provide fresh insights into GPCR structure and function.

biochemistry↗