Biology subjects

Deng, X.

Publications and source records attributed to Deng, X..

At least 19 recordsLinked to original sources

bioRxiv2026

Spatiotemporal Heterogeneity of HPV Integration Architectures Drive Oncogenic Features of Oropharyngeal Cancer

Viral integration is common in human papillomavirus-positive oropharyngeal squamous cell carcinoma (HPV+ OPSCC), but its structural and clinical significance remains unclear. We integrated targeted capture sequencing of 197 HPV+ OPSCCs with long-read nanopore sequencing of 17 tumors and models to characterize HPV-host rearrangements. We developed a novel quantitative informatics framework that classifies integration structures as Type1 (simple, single/low-copy) or Type2 (clustered, high-copy, rearranged). HPV integration occurred in 83% of tumors, with recurrent hotspots including TP63, MYC, CD274, TRAF2, and KMT2C. Type2 events were enriched for HPV E2 disruption, focal human amplifications, preferential transcription, and noncanonical HPV-host RNA fusion isoforms. Type2 tumors showed increased HPV oncogene expression and activation of MYC, NF-{kappa}B/TNF, PI3K-AKT-mTOR, Hippo/YAP-TAZ, and epithelial stemness programs. Multi-region and longitudinal analyses revealed intratumoral heterogeneity and clonal selection of Type2 architectures during progression, supporting integration structure as a potential marker of aggressive behavior and risk stratification.

bioinformatics↗

bioRxiv2026

Unraveling APA dynamics during quiescence transitions reveals Pabp modulation of sod2 expression via APA to regulate cellular quiescence

Quiescence is a reversible proliferation arrest enabling cells to adapt to environmental changes, yet the post-transcriptional mechanisms governing its transitions remain poorly understood. Here, we map genome-wide alternative polyadenylation (APA) dynamics across 15 time points of quiescence transitions in fission yeast using 3'-end RNA sequencing. We reveal that APA undergoes extensive remodeling: driving global 3'UTR lengthening during early quiescence entry, 3' UTR shortening upon quiescence establishment, and progressive reversal to proliferative-state lengths during quiescence exit. Integrating 3' UTR dynamics with differential expression analysis, we identify candidate genes potentially regulated through APA-mediated 3' UTR mechanisms. We demonstrate that sod2, encoding mitochondrial superoxide dismutase, autoregulates its mRNA and protein levels via APA-dependent 3' UTR changes. Disrupting proximal APA site of sod2 in a mitophagy-deficient (atg43{Delta}) background exacerbates quiescence maintenance defects and mitochondrial dysfunction. We further identify Pabp as an upstream regulator of sod2 APA. This study establishes the temporal APA remodeling during quiescence transitions and reveals a Pabp-APA-sod2 regulatory axis governing post-transcriptional control of cellular quiescence.

cell biology↗

bioRxiv2026

Reference-guided pseudotime inference across species and biological contexts

Cells collected at the same chronological age can vary substantially in biological age due to the heterogeneity in the timing of differentiation, speed of maturation, and degeneration. However, existing pseudotime inference methods either disregard chronological time information, or rely on accurate time-series labels within similar species or biological conditions of interest. As a result, both types of strategies often fail to faithfully order cells from biological contexts without reliable time labels, along the desired axis of interest such as human embryonic development or disease progression. Here, we propose Cavebear, a machine learning framework that enables pseudotime inference in a query species or condition guided by scRNA-seq time-series profiles from a reference species or condition. Cavebear achieves more accurate developmental pseudotime inference than existing methods and provides in vivo temporal mapping for in vitro experiments. Furthermore, we illustrate the potential of Cavebear to study cellular-level disease progression in human patients using mouse cancer development models as references. By transferring temporal information across species and conditions, Cavebear enables systematic investigation of biological variation in contexts where such annotations were previously unattainable.

bioinformatics↗

bioRxiv2026

Tumor-tropic E. coli engineered as living T and NK cell engagers

Despite advances in immunotherapy, most solid tumors remain resistant to treatment. Immune cell engagers redirect cytotoxic lymphocytes against cancer, but limited tumor access, immunosuppressive microenvironments and systemic immune activation limit efficacy. Here we develop live immune modulating engagers (LIME), a modular platform where non-pathogenic, tumor-tropic Escherichia coli display tandem single-chain variable fragments targeting a tumor-associated antigen and an activating receptor on T or natural killer cells. LIME bridged effector and tumor cells, induced transcriptional programs of T cell activation, metabolism and proliferation, and enhanced cytotoxicity across cancer cell lines and patient-derived organoids. In mouse models, LIME safely accumulated in tumors, outperformed tarlatamab in small cell lung cancer, and induced durable immunity in lymphoma. RAS inhibition and PD-L1 blockade enhanced LIME activity in pancreatic cancer and induced humoral responses. Multi-lineage immune modulation remained tumor-confined, without organ toxicity. These findings establish LIME as a versatile living therapeutic platform for programmable, tumor-restricted immune orchestration.

bioengineering↗

bioRxiv2026

TROP2-targeting chimeras (TRTACs) for tumor-selective membrane protein degradation and enhanced drug delivery

Extracellular targeted protein degradation (eTPD) systems typically utilize lysosome-targeting receptors (LTRs) to mediate internalization and lysosomal degradation of extracellular and membrane proteins. While multiple LTRs have been discovered, there remains a compelling need to seek for new LTRs, particularly those with clear clinical relevance, to expand the therapeutic potential of eTPD. Here we report trophoblast cell surface antigen-2 (TROP2), a clinically validated tumor-associated antigen, as a promising tumor-selective LTR. We engineer TROP2-targeting chimeras (TRTACs) by genetically fusing a TROP2-binding nanobody to nanobodies against specific target proteins. We show that TRTACs can induce tumor cell-selective degradation of diverse membrane proteins, including epithelial growth factor receptor (EGFR), human epithelial growth factor receptor 2 (HER2), and programmed death-ligand 1 (PD-L1). The EGFR-targeted TRTAC significantly inhibits tumor cell proliferation and shows potent antitumor activity in vivo. We further design TRTAC-drug conjugates (TRTAC-DCs) by attaching cytotoxic payloads to TRTACs, enabling targeted protein degradation together with enhanced drug delivery. TRTAC-DCs show significantly enhanced activity against HER2- and EGFR-positive tumors both in vitro and in vivo, with minimal toxicity observed in normal tissues. These findings establish TROP2 as a robust LTR and provide a versatile eTPD platform with profound translational potential for tumor treatment.

cell biology↗

bioRxiv2026

Remodeling oligodendrocyte lipid metabolism via liver X receptors overcomes inflammatory blockade of remyelination

Multiple sclerosis is characterized by immune-mediated demyelination and inefficient remyelination, owing to impaired differentiation of oligodendrocyte precursor cells (OPCs) into myelinating oligodendrocytes (OLs). Inflammatory cytokines within multiple sclerosis lesions inhibit OPC maturation and induce an immune-like phenotype with antigen-presenting properties, but the underlying mechanisms remain poorly defined. Here, we show that inflammation reprograms OPC lipid metabolism, linking altered metabolism to remyelination failure. In cultured rodent OPCs, interferon-{gamma} (IFN-{gamma}) induced a switch from lipid synthesis to utilization, leading to reduced intracellular fatty acid levels and increased dependence on fatty acid oxidation. Transcriptional analyses confirmed similar lipid metabolic changes in OL-lineage cells cultured from human surgical specimens or isolated from mouse models of inflammatory demyelination and human multiple sclerosis lesions. Enhancing lipid availability in OPCs through oleic acid supplementation or inhibition of fatty acid oxidation attenuated immune-like functions and increased differentiation. Pharmacologic activation of liver X receptor (LXR) transcription factors rebalanced lipid metabolism, suppressed immune-like functions, and overcame IFN-{gamma}-induced differentiation blockade in both mouse and human-derived OPCs. In an adoptive transfer-cuprizone mouse model in which inflammation directly impairs remyelination, LXR activation increased mature OL generation and augmented myelin repair. Together, these findings identify lipid metabolic remodeling as a key mechanism by which inflammation impairs OPC differentiation and highlight LXR activation as a therapeutic approach to enhance remyelination in multiple sclerosis.

neuroscience↗

bioRxiv2026

Large-scale functional coupling and computational modelling reveal frontotemporal hotspots in distributed network connectivity during working memory recognition, encoding, and retrieval

Working memory depends on coordinated activity across distributed brain networks, but how these interactions support recognition, encoding, and retrieval remains unclear. Here, we analyzed intracranial local field potentials from 1,652 sites in 36 epilepsy patients performing a naturalistic card-matching task. Phase-amplitude and phase-phase coupling revealed widespread condition-dependent interactions, with frontal and temporal regions emerging as recurrent network hubs. Event-related analyses showed reproducible within-trial coupling dynamics across participants. Directed phase transfer entropy further identified frequency-specific information flow, including frontal regions acting as a theta-band source and an alpha-band sink. Finally, a time-delay-embedded hidden Markov model identified task-locked latent states with condition-dependent occupancy trajectories and distinct coherence profiles. Together, these results suggest that working memory is implemented through dynamic, directionally organized large-scale networks, in which frontotemporal hubs coordinate flexible transitions among distributed neural states rather than operating in isolation.

neuroscience↗

bioRxiv2026

The CHIP-LMO7-BAG5 complex controls tau clearance and yields repurposed and newly designed therapeutic candidates for Alzheimer's disease

Through cross-species genetic screens, we identified LMO7 as a regulator of tau levels in vivo. LMO7 bridges the E3 ligase CHIP and its inhibitory cochaperone BAG5, suppressing CHIPs ligase activity and limiting tau ubiquitination and degradation. Adult LMO7 knockdown enhances CHIP activity, reduces total and phosphorylated tau, attenuates gliosis, and rescues memory deficits in tauopathy mice. Guided by AlphaFold-derived structural models and AI-based virtual screening, we developed a CHIP-derived competing peptide and identified FDA-approved drugs that disrupt the complex. Viral delivery of the peptide or oral administration of Telmisartan or MPA-2, an optimized Mycophenolic acid derivative, reduced pathogenic tau without toxicity. These findings establish CHIP-LMO7-BAG5 complex as a druggable node in tau homeostasis, with implications for tauopathies including Alzheimers disease, and STUB1-associated ataxias.

neuroscience↗

bioRxiv2026

A human intracranial map of consciousness returning from anesthesia

How consciousness arises from the brain remains a central yet unsolved question. Although substantial effort has been devoted to characterizing the neural correlates of conscious perception during wakefulness, how consciousness re-emerges from unconscious states remains poorly understood. Here, we took advantage of the rare opportunity to record human intracranial local field potentials from propofol-induced general anesthesia through the transition to behavioral engagement and subsequent full wakefulness, capturing both the stable states of unconsciousness and consciousness and the reconstituting neural dynamics that bridge them. Anesthesia cannot be defined by any single electrophysiological signature; rather, it is an organized low-frequency regime characterized by a constellation of coordinated neural phenomena, including aperiodic slow waves, alpha/beta periodicity, global alpha synchronization, and slow-wave-alpha/beta phase-amplitude coupling. Following anesthetic cessation, this regime progressively dissolved as neural excitability and dynamical complexity climbed. The appearance of conscious behavior coincided with a fast and dramatic transformation in high-gamma activity, from stochastic and unpredictable bursts to structured responses that were distributed, task-selective, and event-locked. These findings suggest that the recovery of consciousness is a multiscale reorganization in which distinct neural underpinnings rise and fall. Together, this work charts an electrophysiological map of how conscious cognition is extinguished, reconfigured, and restored in the human brain.

neuroscience↗

bioRxiv2026

Antagonism of stress granules key for SARS-CoV-2 infection and pathogenesis.

Viruses must subvert host responses to facilitate successful infection. While most antiviral responses are associated with interferons, stress granules (SG) are another barrier to viral infection by inducing translation arrest. To combat SG activity, viruses have evolved mechanisms to disrupt formation and disassemble these complexes. Our prior studies identified residues in SARS-CoV-2 NSP3 (Y138/F145) and nucleocapsid (F17) that independently antagonize SG activity. Disrupting these key residues in NSP3 or nucleocapsid attenuated viral replication, but only modestly impacted in vivo pathogenesis suggesting overlap in SG antagonism partially compensate for the individual losses. In this study, we evaluated a SARS-CoV-2 mutant (YF/F17A) that combines the NSP3 and N mutations. We find that loss of both SG antagonizing functions attenuates SARS-CoV-2 replication in vitro. While no changes are seen in type I IFN sensitivity, attenuation corresponds to increased induction of SGs. Importantly, the SARS-CoV-2 YF/F17A mutant has significant attenuation in vivo with reduced viral replication, less weight loss, and limited immune pathology. Notably, infection with the YF/F17A mutant stimulated less interferon and inflammation. Despite these muted host responses, the YF/F17A mutant stimulated robust protection against subsequent challenge with WT SARS-CoV-2. Overall, the study highlights the importance of SG control for SARS-CoV-2 infection and offers a novel, interferon independent target for vaccination and therapeutic treatment going forward. ImportanceThis study demonstrates that SARS-CoV-2 uses multiple mechanisms to block host stress granules during infection. Knocking out both N and NSP3 mediated antagonism of stress granules attenuates viral replication and disease caused by SARS-CoV-2. Importantly, while most therapeutics target key viral processes or induce interferon pathways, this study shows stress granule activation as a novel approach to attenuate and treat coronavirus infection.

microbiology↗

bioRxiv2026

Distinct defense strategies against interbacterial antagonism underpin Acinetobacter persistence in polymicrobial environments

Despite intense interbacterial antagonism mediated by mechanisms such as the type VI secretion system (T6SS), pathogenic Acinetobacter frequently persist within highly competitive polymicrobial infections. How these pathogens navigate such hostile environments to achieve co-existence remains poorly understood. Here, we show that pathogenic Acinetobacter employ distinct, multifaceted strategies to resist elimination by both distantly related competitors and closely related kin. T6SS-active strains outcompete heterologous bacteria by deploying a large and diverse repertoire of antibacterial effectors. In contrast, some naturally T6SS-deficient strains resist exogenous T6SS attacks by elaborating a unique, high-density polysaccharide capsule (KL34) that functions as an effective physical shield. Most intriguingly, we uncover a mechanism that prevents lethal competition among kins. A conjugative multidrug-resistant plasmid encoding T6SS repressors is transferred into aggressive strains upon T6SS-mediated attack, leading to suppression of their antibacterial activity. We also found that conjugation is induced by T6SS attack, which effectively suppresses attacking kin and promotes co-infection in vivo. Together, these findings reveal a dynamic and multilayer defense program that enables Acinetobacter to withstand interbacterial warfare while facilitating co-existence. Our study establishes a paradigm in which damage-triggered plasmid transfer enforces targeted suppression, reshaping microbial interactions in polymicrobial communities.

microbiology↗

bioRxiv2026

Autism associated Cntnap2 deletion disrupts vestibular sensory signaling and spatial cognition in mice

Autism spectrum disorder (ASD) is frequently accompanied by sensory and motor abnormalities, including impaired balance, postural control, and spatial orientation, that are often attributed largely to altered central circuitry. Emerging evidence, however, suggests that peripheral sensory dysfunction can also shape ASD related behavioral phenotypes. Here, we tested whether loss of the ASD associated gene Cntnap2/Caspr2 alters vestibular signaling in Cntnap2-/- mice. Developmental transcriptomic analysis showed that Cntnap2 is expressed in vestibular sensory organs and increases during the first postnatal month, coincident with vestibular pathway maturation. Vestibular sensory evoked potentials revealed reduced response amplitudes and prolonged latencies in Cntnap2-/- mice, indicating impaired peripheral afferent responses to transient linear acceleration. Cntnap2-/- mice also showed delayed contact righting, reduced ocular counter roll, and increased hindlimb slips and compensatory tail excursions during balance beam walking, whereas rotational vestibulo-ocular reflex gain and phase were preserved. These vestibular and balance abnormalities were accompanied by reduced novel arm preference in the Y maze and severe impairment of Barnes maze acquisition, consistent with impaired spatial learning. Together, these findings identify Cntnap2/Caspr2 as a regulator of vestibular sensory signaling and support a model in which disrupted peripheral vestibular input, likely acting together with central effects of Cntnap2 loss, contributes to sensorimotor and spatial cognitive phenotypes relevant to ASD.

neuroscience↗

bioRxiv2026

Embryo-scale Visual Cell Sorting reveals a conserved transcriptomic signature of nucleolar size linked to proteostasis

Nucleoli, nuclear speckles and other compartments regulate transcription, RNA processing, and chromatin organization within the nucleus, yet the relationship of their morphology to developmental gene expression programs in vivo is poorly understood. Here, we develop a high-throughput Visual Cell Sorting (VCS) workflow for fixed cells and nuclei that combines antibody-based photoconversion; GPU-accelerated, real-time image analysis; and three-level single-cell combinatorial indexing RNA-seq (sci-RNA-seq3) to link nuclear compartment morphology to single-nucleus transcriptomes at embryo scale. We use VCS to analyze and sort over 1 million mouse embryo-derived nuclei by nucleolar, nuclear speckle, or nuclear size and construct a transcriptional atlas annotated with nuclear compartment phenotypes. Nuclear compartment size varies both between and within lineages and is shaped by proliferation and differentiation. In extracellular matrix protein-producing cell types such as fibroblasts, chondrocytes, and osteoblasts, nucleolar enlargement is uncoupled from cell cycle, and in erythroid cells exhibit a sharp nucleolar contraction preceding cell-cycle exit. We identify a 41-gene transcriptional signature whose expression tracks nucleolar size, enriched for ribosome biogenesis, mitochondrial metabolism, unfolded protein response, stress granule, and ubiquitin-proteasome pathway components. We used this nucleolar transcriptional signature to annotate mouse, zebrafish and human developmental atlases with nucleolar size information, revealing a conserved coupling between nucleolar activity and proteostasis programs. Our work establishes Visual Cell Sorting as a scalable platform for mapping image-based phenotypes to molecular programs; details the relationship between nuclear compartment phenotypes and development; and provides a transcriptional signature to estimate nucleolar size from existing single-cell datasets.

genomics↗

bioRxiv2026

Disease-specific differences in particulate matter handling drive pathogenic responses in human derived nasal epithelial cells

BackgroundParticulate matter (PM) exposure is associated with increased risk and exacerbation of chronic rhinosinusitis (CRS), yet underlying mechanisms remain poorly understood. ObjectiveTo define the epithelial mechanisms by which PM exposure promotes and exacerbates CRS, with a focus on epithelial remodeling, inflammation, barrier dysfunction, and cellular uptake of PM. MethodsHuman nasal epithelial cells obtained from ethmoid tissue of CRS (n = 5) and control donors (n = 4) were cultured at an air-liquid interface and exposed to PM. Single-cell RNA sequencing was performed to characterize PM-induced cellular and transcriptional changes. Protein expression, epithelial barrier integrity, cell death, and intracellular PM uptake were evaluated using biochemical, imaging, and ultrastructural approaches. ResultsUnsupervised clustering identified seven epithelial cell populations. Gene set analysis revealed baseline enrichment of inflammatory and keratinization pathways and reduced ciliogenesis in CRS compared with controls. Although PM induced inflammation and squamous differentiation in controls, the pathogenic responses were significantly amplified in CRS, including uniquely enhanced IL-1 signaling. Transcriptional changes were validated by ELISA, transepithelial electrical resistance, and immunofluorescence, demonstrating increased inflammation, epithelial barrier disruption, and cell death following PM exposure. Transmission electron microscopy revealed increased intracellular PM within membrane-bound organelles. Pre-treatment with an endocytosis inhibitor rescued PM-induced epithelial barrier dysfunction and inflammation. ConclusionCRS epithelium exhibits baseline dysfunction that may predispose it to environmental injury. PM exposure both induces CRS-like epithelial changes in controls and exacerbates disease-associated phenotypes. Key MessagesO_LICompared to controls, CRS nasal epithelium exhibits baseline inflammatory, keratinization, and ciliogenesis abnormalities. C_LIO_LIParticulate matter induces inflammation and squamous differentiation, while amplifying epithelial injury that is more robust in CRS epithelium compared to controls. C_LIO_LIInhibition of dynamin-dependent endocytosis rescues PM-induced epithelial barrier leakiness and inflammation, implicating intracellular particulate matter uptake in disease pathogenesis. C_LI Capsule SummaryParticulate matter induces CRS-like epithelial remodeling in controls and exacerbates inflammation and epithelial barrier dysfunction in CRS nasal epithelium, which can be rescued with endocytosis inhibition. This suggests a mechanistic link between baseline CRS vulnerability, intracellular uptake of particulate matter, and disease pathogenesis.

cell biology↗

bioRxiv2026

Cell-type specific allelic dampening of sex-linked genes in sex chromosome aneuploidy

Common sex chromosome aneuploidies (SCAs) often present with cognitive and cardiovascular dysfunction in humans. To address SCA effects on gene expression and DNA methylation in relevant cell types, we differentiated neural precursor cells (NPCs) and cardiomyocytes (CMs) from human induced pluripotent stem cells (hiPSCs) with different numbers of sex chromosomes, including isogenic and independent lines. As expected, the expression of genes that escape X inactivation (escapees) mostly increases with the number of inactive X chromosomes (Xi). However, allelic analysis shows dampening of escapees specifically on the Xi in XXY compared to XX in both NPCs and CMs, revealing a novel type of dosage compensation in SCA. In contrast, Y-linked gene expression is higher in XXY versus XY NPCs, but the opposite is observed in CMs. This may explain the greater number of differentially expressed autosomal genes in NPCs versus CMs with an added Y chromosome, while effects of added X chromosomes are similar between cell types. Concordantly, changes in autosomal DNA methylation are mainly driven by the presence of a Y chromosome. These findings highlight the cell-type specificity of sex-linked and autosomal gene regulation in SCA conditions. HighlightsO_LISex chromosome aneuploidy induces cell-type specific changes in gene expression C_LIO_LIDampening of the inactive X chromosome in XXY alleviate X overexpression C_LIO_LIHigh Y-linked gene expression in XXY neuronal precursor cells but not cardiomyocytes C_LIO_LISex chromosome aneuploidy disrupts sex biases in autosomal gene expression C_LI

molecular biology↗

bioRxiv2026

Genomic diversification underlies the broad ecological range of Salmonella enterica serotype Typhimurium

Salmonella Typhimurium is a versatile foodborne pathogen with a broad ecological range, making it an ideal model to better understand pathogen adaptations that allow them to infect multiple hosts and persist across environments. Here, we analyzed 595 genomes of S. Typhimurium representing three food animal sources (bovine, swine, and poultry) and one non-food animal source (wild birds). We found that S. Typhimurium from food animal sources generally had a more open pangenome and harbored more antimicrobial resistance genes (ARGs). Notably, swine isolates exhibited the most open pangenome and the highest prevalence of ARGs, patterns that were associated with a greater presence of mobile genetic elements, particularly plasmids. Despite similar core genome sizes, S. Typhimurium from different sources displayed distinct patterns of positive selection in the core genome that varied in frequency and targeted functional categories. In contrast, although accessory genome sizes varied substantially across sources, the frequency of positive selection remained similar. Using machine learning, we identified source-predictive genetic variants, many of which are associated with stress-response functions. These findings suggest that gain and loss of accessory genes and positive selection acting on core genes support differential adaptation in S. Typhimurium, potentially contributing to its broad ecological range.

genomics↗

bioRxiv2026

Structural Basis of Mitochondrial Transcription Regulation via Interactions of PolRMT and TFAM with Upstream Promoter DNA

Mitochondrial DNA (mtDNA) transcription is essential for cellular energy production and is carried out by a streamlined transcription system in which transcription factor A (TFAM), transcription factor B2 (TFB2M), and the mitochondrial RNA polymerase (PolRMT) assemble at defined promoters to initiate transcription. Previous structural studies elucidated the core initiation mechanism but relied on truncated promoter templates that excluded upstream regulatory DNA interactions. Here, we present two conformations of mitochondrial transcription initiation complexes assembled on the heavy-strand promoter (HSP): a TFAM-bound complex with extended upstream DNA and a TFAM-free complex containing short linear DNA. The TFAM-bound structure reveals a transcription-stimulatory interface between PolRMT and the upstream promoter region (UPR) enabled by TFAM-induced promoter bending. Consistent with this structural observation, UPR truncation reduces transcription from all mtDNA promoters, an effect abolished by mutation of the PolRMT interface. In contrast, the TFAM-free structure reveals a transcription-inhibitory interaction of linear upstream DNA with the PolRMT tether helix, which would sterically clash with TFAM binding. Deletion of the tether helix increases off-target transcription, supporting an autoinhibitory role that enhances promoter specificity. Together, these findings reveal how interactions of TFAM and PolRMT with upstream promoter DNA influence activity and specificity of mitochondrial transcription initiation.

biochemistry↗

bioRxiv2026

Heterogeneous signaling pathways are critical for the persistence of memory T cells in spleen and bone marrow

Persistence of memory T lymphocytes, in the apparent absence of antigen, is a hallmark of immune memory and key to adaptive immunity to recurrent infections. The signaling pathways ensuring survival and quiescence of the memory T cells are largely enigmatic. Here we show, by inhibition in vivo, that persistence of surface CD69+KLF2-tissue-resident memory T cells of murine bone marrow and spleen is blocked by antibodies to the integrins VLA-4 and LFA-1, connecting the memory T cells to VCAM1 and ICAM1 of stromal cells. Persistence requires the PI3K/AKT signaling pathway, since it is blocked by Wortmannin, and it involves PI3K-dependent survival genes. Surface CD69-KLF2+ memory T cells of the bone marrow are also dependent on integrin-mediated contact to stromal cells. Their persistence critically depends on the NF-kB pathway, their PI3K signaling pathway is not relevant. Blocking Jak1 and 3 of the interleukin-7 and -15 signaling pathways does affect memory T cells of the spleen, but not those of the bone marrow. Thus, tissue-resident KLF2+ and KLF2-memory T cells, and memory T cells of spleen and bone marrow, use different signaling pathways, adapting them to their respective tissues and reflecting an unexpected heterogeneity in the molecular mechanisms of persistence.

immunology↗