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Singh, H.

Publications and source records attributed to Singh, H..

At least 37 records · Page 2Linked to original sources

Global climate gradients structure soil Legionella diversity, relative abundance and pathogen distributions

Legionnaires disease has increased sixfold since 2000 in the United States, yet environmental reservoirs such as soils remain understudied sources of infection. It remains unclear how the diversity and abundance of environmental pathogens, such as Legionella, will shift as the climate continues to change. Here, we utilize 4,287 publicly available global soil 16S rRNA gene amplicon datasets to analyze how the distribution of the genus Legionella, including pathogenic lineages, varies across continental-scale biogeographic regions and along climatic and geochemical gradients. Legionella relative abundance increased across the joint precipitation-air temperature gradient, and mixed-effects modeling indicated that the chance of detecting Legionella in soils increased substantially when annual precipitation reached [~]500 mm. Legionella diversity was characterized by high spatial turnover, with the majority of abundant ASVs restricted to individual regions despite broad phylogenetic representation across the genus. Further, fewer than 2% of our 16S-derived Legionella sequences matched ASVs corresponding to characterized species, and the clinically dominant species L. pneumophila was rarely detected. In contrast, ASVs matching several other known pathogens (L. longbeachae, L. anisa, L. bozemanae, L. cincinnatiensis) were orders of magnitude more common than L. pneumophila in soils. Moreover, pathogenic Legionella ASVs were detected significantly more frequently at warmer and wetter conditions. Collectively, our findings suggest that Legionella relative abundance and diversity in soils, especially pathogenic lineages, are shaped by both dispersal and climatic filtering. As temperature and precipitation regimes shift in the future, our results imply that soils should be an important pathogen source to monitor and that Legionella species beyond L. pneumophila warrant increased ecological and public health attention.

microbiology↗

Integrated inference of cancer gene expression from cell-free plasma chromatin

Gene expression is a defining determinant of tumor identity, behavior, and therapeutic response, yet remains challenging to measure noninvasively. Here, we introduce APEX (Associating Plasma Epigenomic features with eXpression), a framework for inferring expression from circulating cell-free chromatin. Trained on [~]270,000 gene-sample pairs from matched tumor RNA-seq and plasma cfChIP-seq across multiple cancers and validated on >15 unseen cancer subtypes, APEX accurately infers cancer gene expression across a range of tumor fractions and outperforms existing plasma-based approaches by integrating positional histone mark and DNA fragmentation patterns across promoters and gene bodies. Using plasma alone, APEX enables classification of prognostically relevant basal and classical pancreatic cancer subtypes and identifies plasma-inferred NECTIN4 expression as a biomarker of response to enfortumab vedotin in metastatic bladder cancer. Together, these findings establish APEX as a biopsy-free approach for profiling tumor transcriptional states and extend liquid biopsy beyond genomic alterations to clinically relevant gene expression programs.

genomics↗

Regulatory network architecture constrains inflammatory responses in tissue-resident alveolar macrophages

Macrophages across different tissues exhibit remarkable functional diversity while maintaining core innate immune-cell programming. These complex programs are governed by gene regulatory networks, in which precise transcription factor activity tunes the expression of functionally relevant gene modules. Although the contributions of individual transcription factors have been well characterized, the higher-order regulatory interactions that coordinate tissue-resident macrophage identity and inflammatory response regulation remain poorly understood. Here, we integrate single-cell RNA-seq data with ATAC-seq profiling and deep-learning-based chromatin accessibility modeling to infer gene regulatory network architectures in tissue-resident versus recruited monocyte-derived alveolar macrophages under inflammatory stress. Our results suggest that inflammatory responses are more restrained in tissue-resident alveolar macrophages compared with recruited macrophages due to a stabilizing regulatory network architecture involving PU.1 and CEBP/{beta}. This work advances our understanding of functional plasticity in tissue-resident macrophages and their role in host defense.

immunology↗

The mechanosensitive protein Zyxin influences Hippo signalling and tissue growth via adherens junctions and basal spot junctions in Drosophila

Physical forces like tension and compression have a central role in the growth and morphogenesis of tissues. Cell-cell junctions and the actin cytoskeleton are key mediators of physical forces and influence activity of signalling networks like the Hippo pathway. Here, we show that the mechanosensitive proteins Zyxin and Ajuba work in concert to limit Hippo signalling and promote Drosophila epithelial tissue growth. Zyxin recruits both Ajuba and the central Hippo pathway kinase Warts to adherens junctions and basal spot junctions, and limit Warts activity by segregating it from Hippo pathway activator proteins. Zyxin also promotes the transmission of actomyosin tension to adherens junctions in growing epithelial tissues, indicating conservation of this function. Thus, we provide new insights into how Zyxin couples mechanical cues and Hippo pathway-dependent tissue growth and highlight the importance of basal spot junctions and their associated actomyosin network in epithelial tissue development.

developmental biology↗

Biological signatures of history: Examination of composite biomes and Y chromosome analysis from da Vinci-associated cultural artifacts

Cultural heritage objects can accumulate DNA from materials, environments, and repeated human contact, but biomolecular profiling of such items is constrained by nondestructive sampling requirements, ultra-low biomass, and high contamination risk. Here we present a minimally invasive workflow that integrates gentle swab collection, low- input whole-metagenome sequencing, taxonomic profiling, and Y-chromosome analyses to recover "biological signatures of history" from Renaissance-era artwork and archival correspondence associated with ancestors of Leonardo da Vinci. Across artifacts, we recovered heterogeneous mixtures of microbial and eukaryotic DNA (including bacteria, fungi, plants, and viruses) consistent with composite "biomes" that reflect differences in substrate, storage, conservation treatments, and handling. Multivariate comparisons show reproducible sample-to-sample separations. In parallel, we assessed human Y-chromosome signal using a panel of [~]90,000 phylogenetically informative markers and partial Y-STR profiling where feasible. Across multiple independent swabs from Leonardo da Vinci-associated items, the obtained Y chromosome marker data suggested assignments withing the broader E1b1/E1b1b clade. However, the control samples also indicate mixed contributions consistent with modern handling and other sources. Together, these data demonstrate the feasibility as well as limitations of combining metagenomics and human DNA marker analysis for cultural heritage science, providing a baseline workflow for future conservation science studies and hypothesis-driven investigations of provenance, authentication and handling history.

genomics↗

Arsenic Trioxide Underpins Delayed Neuroinflammation and Impaired Synaptic Integrity involving Integrative Stress Response Signaling

Arsenic trioxide (ATO), an industrial and environmental chemical with potential for accidental or intentional exposure, exerts profound neurotoxic effects. Its single acute exposure has been linked to delayed neurological and neurodegenerative outcomes. However, the molecular and cellular pathways driving these long-term manifestations remain poorly defined. In this study, combining human iPSC-derived neuronal and in vivo mouse model, we uncovered that the acute ATO exposure activates cellular stress pathway, which drives long-term neurotoxic and associated functional outcomes. We found that ATO induces integrated stress response (ISR) signaling in human iPSC-derived neurons. To model the impact of accidental ATO exposure in vivo, we administered a single high dose of ATO to C57BL/6J wild type mice. Four weeks post-treatment, ATO-exposed mice displayed neuropsychological symptoms and cognitive deficits. Brain analyses of ATO-challenged mice revealed elevated ISR activity marked by the increased phosphorylation of PERK and eIF2 and upregulation of the transcription factors, CHOP and ATF4. Transcriptomic profiling using bulk RNAseq revealed activation of pathways associated with stress and neuroinflammatory responses. Consistently, increased DNA damage and dysregulation of the STING-mediated innate immune response were also found in the brain of ATO-challenged mice. Pharmacological inhibition of the ISR with a small-molecule inhibitor, ISRIB mitigated ISR activation and preserved synaptic integrity in mouse hippocampal cells. In conclusion, our data identify ISR activation and DNA damage-driven immune dysregulation as key pathogenic drivers of ATO-induced delayed neurotoxicity and cognitive deficits and highlight ISR inhibitors as promising therapeutics to mitigate these effects.

neuroscience↗

Harnessing cGAS-STING signaling to counteract the genotoxic-immune nexus in tauopathy

Tauopathies are progressive neurodegenerative disorders characterized by aberrant tau aggregation, cognitive decline, and persistent neuroinflammation, yet the mechanisms driving neuroinflammation and disease progression remain incompletely understood. Here, utilizing human postmortem AD brains and a mouse model of tauopathy, we report that genotoxic stress-induced cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) immune pathway form a self-amplifying loop that fuels neuropathology and cognitive deficits. Targeted disruption of this cycle through either genetic deletion of cGAS or pharmacological inhibition of STING restores immune homeostasis and attenuates tau pathology and cognitive deficits. Our results showed a significant accumulation of DNA double-strand breaks (DDSBs) and impaired DNA repair function, alongside elevated cGAS-STING signaling and type I interferon (IFN-I) responses in human AD brains compared to non-AD. In the PS19 transgenic (PS19Tg) mouse model of tauopathy, we found significantly elevated levels of DDSBs and altered expression of DNA repair proteins during early stages of disease, which preceded the dysregulation of cGAS-STING signaling and emergence of significant neuropathology in the later stage. Interestingly, genetic deletion of cGAS shifted microglial polarization from a pro-inflammatory M1 phenotype toward an anti-inflammatory M2 state, accompanied by a reduction in IFN-I signaling and improved cognitive performance in PS19Tg mice. Pharmacological STING inhibition reshaped the transcriptomic landscape, revealing selective regulation of pathways governing synaptic plasticity, and immune responses. This transcriptional reprogramming was accompanied by suppression of inflammatory responses, reduction in synaptic pathology, and attenuation of tau pathology in PS19Tg mice, underscoring STING as a therapeutic target for tauopathy. In conclusion, our findings reveal that genotoxic-immune crosstalk drives neuroinflammation and tau pathology and identify a conserved, druggable cGAS-STING axis that can be targeted to impede or slow disease progression in tauopathies. O_FIG O_LINKSMALLFIG WIDTH=184 HEIGHT=200 SRC="FIGDIR/small/678980v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@1339c89org.highwire.dtl.DTLVardef@16a1d5borg.highwire.dtl.DTLVardef@1ad4631org.highwire.dtl.DTLVardef@db4615_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

Respiratory exposure to inert particulate matter during pregnancy leads to oxidative stress and cardiac proteome remodeling

Withdrawal StatementThe authors have withdrawn this manuscript because upon peer review major revisions have been identified as needed to ensure that the conclusions are in par with the presented data. Current studies are ongoing to provide a more complete version of the manuscript for peer review publication. Therefore, the authors do not wish this work to be cited as reference for the project in its current form. If you have any questions, please contact the corresponding author.

molecular biology↗

PRDM1 shapes germinal center B-cell clonal diversity by gating chromatin accessibility during light-to-dark zone transition

Germinal-center (GC) B-cell responses are defined by many positive regulators of affinity maturation, but few components that restrain clonal dominance, notably Nr4a1, are known. We reveal an unsuspected role for PRDM1 (BLIMP1), a plasma-cell determinant, as a feedback regulator of affinity maturation. Single cell RNA-seq and BCR-seq showed that B- cell-specific Prdm1 loss drives an exaggerated GC reaction with larger clones, increased somatic hypermutation, and greater clonal dominance, independent of Nr4a1. Single cell chromatin profiling with base-resolution modelling indicated that PRDM1 represses expression of BCR-signaling genes and gates chromatin accessibility at ISRE, EICE, NF-{kappa}B, and POU (Oct) motifs. In the absence of PRDM1, enhanced engagement of signaling-inducible transcription factors promotes G1-S transition during light-zone (LZ) selection and fuels dark-zone (DZ) expansion. Thus, PRDM1 attenuates BCR signaling and constrains the LZ[->]DZ transition, fine-tuning clonal competition thereby maintaining repertoire diversity. The chromatin-encoded checkpoint could be leveraged to modulate vaccine responses.

immunology↗

Aging-Driven Immunosuppression: The Role of Tregs in the Ovarian Tumor Microenvironment

Epithelial ovarian cancer (EOC) incidence and mortality increase with age, driven in part by chronic inflammation, diminished T cell output, and heightened regulatory T cell (Treg)-mediated immunosuppression. In aged EOC-bearing mice, we observed reduced survival, accompanied by impaired CD4 and CD8T cell responses and a marked expansion of FOXP3 Tregs exhibiting elevated IL-10 and TGF{beta} expression. Metabolic profiling revealed enhanced oxidative phosphorylation in Tregs from aged mice, along with a fivefold increase in intracellular succinate levels. This accumulation of succinate within the aged tumor microenvironment was found to potentiate Treg suppressive function. Notably, pharmacologic inhibition of -ketoglutarate dehydrogenase reversed this effect, restoring effector T cell activity. These findings highlight succinate driven metabolic reprogramming as a central mechanism of age related Treg dysfunction in EOC and suggest that targeting succinate metabolism may offer a promising strategy to rejuvenate antitumor immunity in elderly patients.

immunology↗

Expanding the DNA Motif Lexicon of the Transcriptional Regulatory Code

Transcriptional regulatory sequences in metazoans contain intricate combinations of transcription factor (TF) motifs. Stereospecific arrangements of simple motifs constitute composite elements (CEs) that enhance DNA-protein interaction specificity and enable combinatorial regulatory logic. Despite their importance, CEs remain underexplored. We advance CE discovery and functional characterization by developing an integrated framework that combines computational prediction, experimental testing and deep learning. The extended TF motif catalog comprises both synergistic and counteracting CEs, which are supported by evidence of TF binding in vivo and in vitro. A deep learning model GRACE trained on customized massively parallel reporter assays learns the lexicon of CEs at single-nucleotide resolution. Comparative analysis with a neural network model trained on chromatin accessibility demonstrates striking convergence and distinctions within the expanded regulatory lexicon, enabling joint predictions of motif contributions and the impact of variants on chromatin structure and transcriptional activity in diverse cellular contexts.

genomics↗

Serum exosome miR-150-5p in rheumatic heart disease-associated angiogenesis

The focus of this study is on Rheumatic heart disease (RHD), an autoimmune consequence of rheumatic fever leading to mitral valve damage. Aim is to explore the role of exosomes derived from RHD patients in promoting angiogenesis during RHD pathogenesis. Exosomes were isolated via column chromatography from the pericardial fluid (PF) and serum of RHD patients, pericardial fluid from non-RHD patients undergoing coronary artery bypass grafting (CABG) surgery, and serum of healthy individuals. These exosomes were characterized by transmission electron microscopy (TEM) and western blotting. Human umbilical vein endothelial cells (HUVECs) cultured from umbilical cord(s), were treated with purified exosomes from RHD, CABG patients or healthy individuals. Exosome treatment induced morphological changes in HUVECs, including elongation and tube-like structure formation. The qRT-PCR gene expression analysis revealed significant upregulation of angiogenic markers (VEGF-A 2.7-fold, MMP2 1.5-fold) and inflammatory cytokine (IL-4 15.17-fold), in HUVECs stimulated with RHD serum exosomes. Conversely, there was downregulation of anti- angiogenic genes (RASA-1 0.65-fold and endostatin 0.4-fold). Notably, elevated levels of miR- 150-5p (34.29 + 9.524-fold mean difference; p= 0.0007) were detected in serum-derived exosomes from RHD patients compared to healthy controls. Stimulation of HUVECs with RHD serum exosomes resulted in reduction in the expression of TP53 (0.227-fold; p= 0.006), a known target of miR-150-5p. Furthermore, transfection of HUVECs with miR-150-5p mimics induced the formation of angiogenic endothelial tubes, underscoring the role of miR-150-5p in promoting angiogenesis. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=128 SRC="FIGDIR/small/659484v1_ufig1.gif" ALT="Figure 1000"> View larger version (27K): org.highwire.dtl.DTLVardef@1520e92org.highwire.dtl.DTLVardef@3aa03aorg.highwire.dtl.DTLVardef@ed6e1dorg.highwire.dtl.DTLVardef@1d85231_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

CFTR mutation leads to intrinsic dysfunction in neutrophils from people with Cystic Fibrosis

Cystic fibrosis (CF), a common genetic disease, is caused by a defective CF-transmembrane conductance regulator (CFTR). People with CF (pwCF) are prone to develop infections by opportunistic pathogens, including Burkholderia cenocepacia, leading to chronic inflammation and lung function loss. Neutrophils, the most abundant cells in the chronically inflamed lungs of pwCF, release granular proteins and oxidative products that contribute to tissue damage. The CFTR modulators are a new treatment for pwCF aiming to correct the subcellular location and function of the CFTR ion channel. The triple modulator combination of Elexacaftor, Tezacaftor, and Ivacaftor (ETI) or Trikafta(R) has significantly improved clinical symptoms and overall provided a better quality of life for pwCF. The mechanism by which the CFTR modulators help to restore the antimicrobial functions of neutrophils is unknown. The present study demonstrates that neutrophils functionally express CFTR and reveals how ETI modifies subcellular CFTR trafficking in CF neutrophils. In addition, ETI treatment reduces intracellular chloride levels in human neutrophils, indicating activation of CFTR-dependent chloride efflux (outflow). Finally, ETI treatment also reestablished the intracellular antimicrobial killing of CF neutrophils by potentiating NADPH oxidase activity and producing Neutrophil Extracellular Traps (NETs). Together, our findings suggest that CFTR has an essential role in controlling neutrophil functions and that the CFTR modulators improve the health of pwCF by restoring the antimicrobial functions of CF neutrophils. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=117 SRC="FIGDIR/small/656500v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@8469b5org.highwire.dtl.DTLVardef@1380609org.highwire.dtl.DTLVardef@1145117org.highwire.dtl.DTLVardef@d7c0a2_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstract.C_FLOATNO (A) The F508del defective CFTR protein cannot reach the plasma membrane in CF neutrophils, which increases the intracellular concentrations of Cl- ions, and allows other ions to be internalized, including Na+ and Ca2+. This ionic imbalance affects the NADPH oxidase, leading to a reduced preactivation response and consequently impacting NADPH oxidase-dependent antimicrobial mechanisms, including intracellular antimicrobial killing and NETosis. (B) Treating with ETI restores the CFTR expression in the plasma membrane of CF neutrophils, increasing the Cl- efflux and regulating the intracellular levels of Na+ and Ca2+, leading to correcting the NADPH oxidase, which results in potentiating the intracellular antimicrobial killing and NETosis. BiorenderTM tools generated the images. C_FIG

immunology↗

Unique TMJ-specific transcriptomic signature and its medial layer: Implications in osteoarthritis

ObjectivesOsteoarthritis (OA) is a debilitating joint disease that affects millions of people worldwide, with the temporomandibular joint (TMJ) and knee joint being prominently affected. Despite its prevalence, TMJ-OA remains understudied. This study aimed to investigate the transcriptional signature of the TMJ compared to that of the knee joint and to explore transcriptional differences in the medial and superficial layers of the TMJ-OA. DesignSix-month-old C57BL/6J mice TMJ and knee samples were collected. Goat TMJ superficial and medial layer cartilage was separated and treated with IL-1{beta}. All samples were subjected to bulk RNA sequencing followed by differential expression and gene set enrichment analysis. ResultsWe identified 4,031 protein-coding genes differentially expressed in the TMJ compared to the knee, with significant enrichment of neuronal system genes and lower enrichment of innate immune system genes. Key osteoarthritis biomarkers such as Mmp13, Postn, and Col1a1 were more highly expressed in the TMJ, indicating a higher vulnerability to OA development. IL-1{beta} treatment in goat TMJ chondrocytes mimicked the natural TMJ-OA-like transcriptional changes and immune responses, which are also observed in the rabbit TMJ-OA model. This validated the in vitro goat TMJ-OA model. The IL-1{beta}-treated goat TMJ medial cartilage layer was enriched in OA-associated transcription factors (TFs), senescence genes, and epigenetic regulators. ConclusionOur study demonstrated the unique transcriptomic signature of the TMJ compared with the knee joint, highlighting its vulnerability to OA and pain. These findings provide valuable insights into the molecular mechanisms of TMJ and offer a resource for potential therapeutic target selection for TMJ-OA treatment. HighlightsO_LISignificant enrichment of neuronal system genes and lower enrichment of innate immune system genes in temporomandibular joint. C_LIO_LIKey osteoarthritis biomarkers such as Mmp13, Postn, and Col1a1 have higher expression in temporomandibular joint, indicating a higher vulnerability to osteoarthritis development. C_LIO_LIInterleukin-1beta treatment in goat temporomandibular joint medial layer cartilage mimics natural temporomandibular joint osteoarthritis-like transcriptional changes and immune responses observed in rabbit temporomandibular joint osteoarthritis model. C_LI

molecular biology↗

Scalable TCR synthesis and screening enables antigen reactivity mapping in vitiligo

T cell receptors (TCRs) mediate antigen recognition in adaptive immunity, yet large-scale mapping of TCR-antigen interactions remains a major challenge. Current approaches to synthesize and functionally screen TCRs remain technically complex and limited in throughput. We introduce a modular strategy, TCRAFT, to rapidly construct tens of thousands of TCRs for <$1 each while maintaining TCR-{beta} pairing with >99% accuracy. We integrate this approach with a high-throughput antigen discovery platform to enable library-on-library TCR-antigen screening. We reconstruct and screen 3,808 TCRs from vitiligo lesions, linking TCR specificity to transcriptional phenotypes for antigen-reactive T cells. To demonstrate scalability, we synthesize and screen 30,810 TCRs from donors with pancreatic ductal adenocarcinoma to capture antigen-specific TCRs. This workflow reduces the cost and complexity of large-scale TCR screening, enabling the expansion of the known landscape of antigen-specific TCRs in vitiligo with a method that can be readily extended to other immunological applications.

immunology↗

Cell cycle-coupled transcriptional network orchestrates human B cell fate bifurcation

Bifurcation of activated human B cells into plasmablast (PB) and germinal center precursor (preGC) fates underlies protective and autoimmune antibody responses, yet gene regulatory networks (GRNs) governing the alternative trajectories remain poorly defined. Using temporal single-cell multiomics, we assembled state-specific human B cell GRNs spanning four scales: transcription factor (TF)-to-fate, TF-to-gene, cis-regulatory element (CRE)-to-gene and nucleotide-to-CRE. Applying the framework to in vitro differentiated and tonsil B cells revealed concordant regulatory architectures and impacts of in silico TF perturbations. CRISPR perturbations validated many TF-to-fate and TF-to-gene predictions and revealed a mutually repressive BATF-IRF4/PRDM1 network module. The GRNs were used to predict and interpret effects of autoimmune disease variants, uncovering partitioning of disease risk at distinct TF motifs and B cell states. Predicted functional variants were independently supported by chromatin and expression QTLs and reporter assays. A web application enables exploration of B cell regulatory determinants of vaccine responses and autoimmune diseases.

immunology↗

The Response Regulator BqsR/CarR Controls Ferrous Iron (Fe2+) Acquisition in Pseudomonas aeruginosa

Pseudomonas aeruginosa is a ubiquitous, Gram-negative bacterium that forms biofilms and is responsible for antibiotic-resistant hospital-acquired infections in humans. The P. aeruginosa BqsRS two-component system regulates biofilm formation and dispersal by sensing extracytoplasmic Fe2+, but the mechanistic details of this process are poorly understood. In this work, we report the crystal and solution structures of the PaBqsR response regulator receiver domain, comprising a ({beta})5 response regulator assembly, and the DNA-binding domain, comprising a helix-turn-helix motif. Consistent with its cognate stimulus being Fe2+, we show that PaBqsR binds directly to the promoter region of the feo operon that encodes the bacterial Fe2+ transport system FeoABC. Corroborating these in vitro results, transcriptional studies show that PaBqsR is a global regulator controlling many important genes in PAO1, including the feo operon. Intriguingly, promoter-based assays reveal that PaBqsR is a dynamic regulator that responds to bioavailable Fe2+, likely through the ability of PaBqsR to bind Fe2+ directly via a His-rich motif, independent of the PaBqsS membrane His kinase. This mode of regulation is unprecedented among OmpR-like response regulators but represents an important level of control over Fe2+ acquisition in P. aeruginosa that could be an attractive therapeutic target to treat hospital-acquired infections.

biochemistry↗

Epidermal Resident Memory T Cell Fitness Requires Antigen Encounter in the Skin

CD8+ tissue resident memory T cells (TRM) develop from effectors that seed peripheral tissues where they persist providing defense against subsequent challenges. TRM persistence requires autocrine TGF{beta} transactivated by integrins expressed on keratinocytes. TRM precursors that encounter antigen in the epidermis during development outcompete bystander TRM for TGF{beta} resulting in enhanced persistence. ScRNA-seq analysis of epidermal TRM revealed that local antigen experience in the skin resulted in an enhanced differentiation signature in comparison with bystanders. Upon recall, TRM displayed greater proliferation dictated by affinity of antigen experienced during epidermal development. Finally, local antigen experienced TRM differentially expressed TGF{beta}RIII, which increases avidity of the TGF{beta}RI/II receptor complex for TGF{beta}. Selective ablation of Tgfbr3 reduced local antigen experienced TRM capacity to persist, rendering them phenotypically like bystander TRM. Thus, antigen driven TCR signaling in the epidermis during TRM differentiation results in a lower TGF{beta} requirement for persistence and increased proliferative capacity that together enhance epidermal TRM fitness.

immunology↗