Biology subjects

Li, Q.

Publications and source records attributed to Li, Q..

At least 361 records · Page 20Linked to original sources

bioRxiv2024

Mechanical cues of extracellular matrix determines tumor innervation

Peripheral tumors can establish local autonomic and sensory nerve networks, termed as tumor innervation (TIN), to support tumorigenesis and metastasis. While nerve dependence in cancers is well-established, the mechanisms governing TIN remain unclear. Here, we report that extracellular matrix (ECM) stiffness, a major mechanical abnormality in the tumor microenvironment (TME), is an essential contributor of TIN. In preclinical models, reducing lysyl oxidase-mediated ECM crosslinking lowers tissue stiffness and TIN in pancreatic cancer, while inflammation-induced matrix stiffening boosts the hyperinnervation of the pancreatic precursor lesions. Mechanistically, {beta}1-containing integrins sense the mechanical cues exerted by ECM stiffness, and the translational co-activator YAP1 acts as an essential nuclear relay to induce the expression of neurotropic genes, particularly brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). 3D imaging of the whole cleared pancreas reveals that blockade of mechanosensor integrin {beta}1 or pharmacological inhibition of the mechanotransducer YAP1 effectively reduces TIN. In clinical settings, tumor samples with a dense, crosslinked, and stiffened ECM exhibit significant TIN. In summary, these findings identify ECM stiffness as an important driver of TIN and suggest that targeting integrin {beta}1/YAP1-dependent mechanotransduction may counteract TIN.

neuroscience↗

bioRxiv2024

Pure Nano Genesis: Pioneering Universal Aqueous Nanostrategies from Pure Molecules to Revolutionise Diverse Applications

In this paper, we propose a novel universal approach for the construction of stable and aqueous nanoparticles, Pure Nano systems, comprising solely small conjugated molecules without any excipients. Our experiments confirm that the generation of surface charges plays an essential role during the spontaneous aggregation of conjugated molecules in the process of Pure Nano system fabrication, as it governs growth and confers physiochemical stability to particles at the nano scale. This approach overcomes solubility challenges in highly hydrophobic conjugated molecules by obviating excipients and enabling up to 100% drug loading capacity. Confirmation of this capability stems from the successful preparation of approximately 100 Pure Nano systems, incorporating different combinations of 27 conjugated molecules distinguished by their diverse dissociation types and degrees. The proposed preparation method is robust, simple, fast, and reliable, making it well-suited for large-scale manufacturing due to its array of unique features. This strategy affords a singular, molecular-focused approach, showcasing the intrinsic bioactivity of its constituent molecules while enabling aqueous dispersion for diverse applications. And in vivo experiments confirm the exceptional efficacy of various Pure Nano systems in reinstating dextran sodium sulfate induced acute ulcerative colitis to a healthy state, restoring myocardial ischemia/reperfusion injury to normal levels, and effectively treating cancer in mice with significantly improved median survival rates. This innovative nano drug delivery system represents a groundbreaking advancement with the potential to revolutionise translational nanomedicine. Positioned at the forefront of therapeutic possibilities, it is anticipated to substantially improve the efficacy and safety of nano therapies. This advancement heralds a new era, offering a highly targeted and efficient approach in the treatment of diverse medical conditions.

pharmacology and toxicology↗

bioRxiv2024

Cyborg islets: implanted flexible electronics reveal principles of human islet electrical maturation

Flexible electronics implanted during tissue formation enable chronic studies of tissue-wide electrophysiology. Here, we integrate tissue-like stretchable electronics during organogenesis of human stem cell-derived pancreatic islets, stably tracing single-cell extracellular spike bursting dynamics over months of functional maturation. Adapting spike sorting methods from neural studies reveals maturation-dependent electrical patterns of and {beta}-like (SC- and {beta}) cells, and their stimulus-coupled dynamics. We identified two major electrical states for both SC- and {beta} cells, distinguished by their glucose threshold for action potential firing. We find that improved hormone stimulation capacity during extended culture reflects increasing numbers of SC-/{beta} cells in low basal firing states, linked to energy and hormone metabolism gene upregulation. Continuous recording during further maturation by entrainment to daily feeding cycles reveals that circadian islet-level hormone secretion rhythms reflect sustained and coordinate oscillation of cell-level SC- and {beta} electrical activities. We find that this correlates with cell-cell communication and exocytic network induction, indicating a role for circadian rhythms in coordinating system-level stimulus-coupled responses. Cyborg islets thus reveal principles of electrical maturation that will be useful to build fully functional in vitro islets for research and therapeutic applications.

bioengineering↗

bioRxiv2024

PIGOME: An Integrated and Comprehensive Multi-omics Database for Pig Functional Genomics Studies

In addition to being a major source of animal protein, pigs are important model for the study of development and diseases in humans. During the past two decades, thousands of high-throughput sequencing studies in pigs have been performed using a variety of tissues from different breeds and developmental stages. However, the multi-omics database specifically used for pig functional genomic research is still limited. Here, we present a user-friendly database of pig multi-omics named PIGOME. PIGOME contains seven types of pig omics datasets, including whole-genome sequencing, RNA-seq, miRNA-seq, ChIP-seq, ATAC-seq, bisulfite-seq, and MeRIP-seq, from 6,901 samples and 392 projects with manually curated metadata, integrated gene annotation, and quantitative trait locus information. Furthermore, various explore and browse functions have been established for user-friendly access to omics information. PIGOME implemented several tools to visualize genomic variants, gene expression, and epigenetic signals of a given gene in the pig genome, enabling efficient exploration of spatial-temporal expression/epigenetic pattern, function, regulatory mechanism, and associated economic traits. Collectively, PIGOME provides valuable resources for pig breeding and is helpful for human biomedical research. PIGOME is available at https://pigome.com.

bioinformatics↗

bioRxiv2024

Impaired central pattern generators due to abnormal EPHA4 signaling leads to idiopathic scoliosis

Idiopathic scoliosis (IS) is the most common form of spinal deformity with unclear pathogenesis. In this study, we firstly reanalyzed the loci associated with IS, drawing upon previous studies. Subsequently, we mapped these loci to candidate genes using either location-based or function-based strategies. To further substantiate our findings, we verified the enrichment of variants within these candidate genes across several large IS cohorts encompassing Chinese, East Asian, and European populations. Consequently, we identified variants in the EPHA4 gene as compelling candidates for IS. To confirm their pathogenicity, we generated zebrafish mutants of epha4a. Remarkably, the zebrafish epha4a mutants exhibited pronounced scoliosis during later stages of development, effectively recapitulating the IS phenotype. We observed that the epha4a mutants displayed defects in left-right coordination during locomotion, which arose from disorganized neural activation in these mutants. Our subsequent experiments indicated that the disruption of the central pattern generator (CPG) network, characterized by abnormal axon guidance of spinal cord interneurons, contributed to the disorganization observed in the mutants. Moreover, when knocked down efnb3b, the ligand for Epha4a, we observed similar CPG defects and disrupted left-right locomotion. These findings strongly suggested that ephrin B3-Epha4 signaling is vital for the proper functioning of CPGs, and defects in this pathway could lead to scoliosis in zebrafish. Furthermore, we identified two cases of IS in NGEF, a downstream molecule in the EPHA4 pathway. Collectively, our data provide compelling evidence that neural patterning impairments and disruptions in CPGs may underlie the pathogenesis of IS.

genetics↗

bioRxiv2024

RPA and Rad27 limit templated and inverted insertions at DNA breaks

Formation of templated insertions at DNA double-strand breaks (DSBs) is very common in cancer cells. The mechanisms and enzymes regulating these events are largely unknown. Here, we investigated templated insertions in yeast at DSBs using amplicon sequencing across a repaired locus. We document very short (most [~]5-34 bp), templated inverted duplications at DSBs. They are generated through a foldback mechanism that utilizes microhomologies adjacent to the DSB. Enzymatic requirements suggest a hybrid mechanism wherein one end requires Pol{delta}-mediated synthesis while the other end is captured by nonhomologous end joining (NHEJ). This process is exacerbated in mutants with low levels or mutated RPA (rtt105{Delta}; rfa1-t33) or extensive resection mutant (sgs1{Delta} exo1{Delta}). Templated insertions from various distant genomic locations also increase in these mutants as well as in rad27{Delta} and originate from fragile regions of the genome. Among complex insertions, common events are insertions of two sequences, originating from the same locus and with inverted orientation. We propose that these inversions are also formed by microhomology-mediated template switching. Taken together, we propose that a shortage of RPA typical in cancer cells is one possible factor stimulating the formation of templated insertions.

genetics↗

bioRxiv2024

Unconventional IFNω-like genes dominate the type I IFN locus and the constitutive antiviral responses in bats

Bats are the natural reservoir hosts of some viruses, some of which may spillover to humans and cause global-scale pandemics. Different to humans, bats may coexist with high pathogenic viruses without showing symptoms of diseases. As one of the most important first defenses, bat type I interferon (IFN-Is) were thought to play a role during this virus coexistence and thus were studied in recent years. However, there are arguments that whether bats have a contracted genome locus or constitutive expressed IFNs, mainly due to species-specific findings. We hypothesized that because of the lacking of pan-bat analysis, the common characters for bat IFN-Is have not been revealed yet. Here, we characterized the IFN-I locus for 9 Yangochiroptera bats and 3 Yinpterochiroptera based on the their high quality bat genomes. We also compared the basal expression for 6 bats and compared the antiviral, anti-proliferative activity and thermo-stability of a representative Rhinolophus bat IFNs. We found a dominance of unconventional IFN{omega}-like responses in the IFN-I system, which is unique to bats. In contrast to IFNa-dominated IFN-I loci in the majority of other mammals, bats generally have shorter IFN-I loci with more unconventional IFN{omega}-like genes (IFN{omega} or related IFNa{omega}), but with less or even no IFNa genes. In addition, bats generally have constitutively expressed IFNs, the highest expressed of which is more likely an IFN{omega}-like gene. Likewise, the highly expressed IFN{omega}-like protein also demonstrated the best antiviral activity, anti-proliferative activity or thermo-stability, as shown in a representative Rhinolophus bat species. Overall, we revealed pan-bat unique characteristics in IFN-I system, which provide insights into our understanding of the innate immunity that contribute to a special coexistence between bats and viruses.

immunology↗

bioRxiv2024

From Sight to Insight: A Multi-task Approach with the Visual Language Decoding Model

Visual neural decoding aims to unlock the mysteries of how the human brain interprets the visual world. While early studies made some progress in decoding visual activity for singular type of information, they failed to concurrently reveal the multi-level interweaving linguistic information in the brain. Here, we developed a novel Visual Language Decoding Model (VLDM) capable of decoding categories, semantic labels, and textual descriptions from visual perceptual activities simultaneously. We selected the large-scale NSD dataset to ensure the efficiency of the decoding model in joint training and evaluation across multiple tasks. For category decoding, we achieved the effective classification of 12 categories with an accuracy of nearly 70%, significantly surpassing the chance level. For label decoding, we attained the precise prediction of 80 specific semantic labels with a 16-fold improvement over the chance level. For text decoding, the scores of the decoded text surpassed the corresponding baseline levels by remarkable margins on six evaluation metrics. This study contributes significantly to extensive applications in multi-layered brain-computer interfaces, potentially leading to more natural and efficient human-computer interaction experiences.

neuroscience↗

bioRxiv2024

Prevalence and preferred niche of small eukaryotes with mixotrophic potentials in the global ocean

Unicellular eukaryotes that are capable of phago-mixotrophy in the ocean compete for inorganic nutrients and light with autotrophs, and for bacterial prey with heterotrophs. In this study, we ask what are the overall prevalence of eukaryotic mixotrophs in vast open oceans, and how the availability of inorganic nutrients, light, and prey affects their relative success. We utilized the Tara Oceans eukaryotic 18S rRNA gene and environmental context variables dataset to conduct large-scale field analysis. We also performed isolate-based culture experiments to verify growth and nutritional resource relationships for representative mixotrophic taxa. The field analysis suggested that the overall prevalence of mixotrophs was negatively correlated with nutrient concentrations and positively associated with light availability. Concentrations of bacterial prey also presented somewhat correlation with mixotrophs but to a less extent. In comparison, the culture experiments demonstrated a taxa-specific relationship between mixotrophic growth and nutrition resources, i.e., the growth of one group was significantly dependent on light availability while the other group was less affected by light when they received sufficient prey. Both groups were capable of growing efficiently with low inorganic nutrients when receiving sufficient prey and light. Therefore, our field analysis and culture experiments both suggest that phago-mixotrophy for ocean eukaryotes is seemingly to be an efficient strategy to compensate nutrient deficiency but unnecessarily light limitation. This study collectively revealed a close relationship between abiotic and biotic nutritional resources and the prevalence of trophic strategies, shedding light on the importance of light and nutrients for determining the competitive success of mixotrophs versus autotrophic and heterotrophic eukaryotes in the ocean.

microbiology↗

bioRxiv2024

RNA Splicing Junction Landscape Reveals Abundant Tumor-Specific Transcripts in Human Cancer

RNA splicing is a critical process governing gene expression and transcriptomic diversity. Despite its importance, a detailed examination of transcript variation at the splicing junction level remains scarce. Here, we perform a thorough analysis of RNA splicing junctions in 34,775 samples across multiple sample types. We identified 29,051 tumor-specific transcripts (TSTs) in pan-cancer, with a majority of these TSTs being unannotated. Our findings show that TSTs are positively correlated with tumor stemness and linked to unfavorable outcomes in cancer patients. Additionally, TSTs display mutual exclusivity with somatic mutations and are overrepresented in transposable element-derived transcripts possessing oncogenic functions. Importantly, TSTs can generate neoepitopes that bind to MHC class I molecules for immunotherapy. Moreover, TSTs can be detected in blood extracellular vesicles from cancer patients. Our results shed light on the intricacies of RNA splicing and offer promising avenues for cancer diagnosis and therapy. In briefThis study thoroughly analyzed RNA splicing junctions in 34,775 samples and identified 29,051 tumor-specific transcripts (TSTs), which may serve as novel cancer driver genes, neoantigens, and circulating biomarkers. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=153 SRC="FIGDIR/small/579246v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@7e1db2org.highwire.dtl.DTLVardef@1cfbe81org.highwire.dtl.DTLVardef@1e427e1org.highwire.dtl.DTLVardef@1f655f5_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

A Simple and Scalable Zebrafish Model of Sonic Hedgehog Medulloblastoma

Medulloblastoma (MB) is the most common malignant brain tumor in children and is stratified into three major subgroups. The Sonic hedgehog (SHH) subgroup represents [~]30% of all MB cases and has significant survival disparity depending upon TP53 status. Here, we describe the first zebrafish model of SHH MB using CRISPR to mutate ptch1, the primary genetic driver in human SHH MB. These tumors rapidly arise adjacent to the valvula cerebelli and resemble human SHH MB by histology and comparative genomics. In addition, ptch1-deficient MB tumors with loss of tp53 have aggressive tumor histology and significantly worse survival outcomes, comparable to human patients. The simplicity and scalability of the ptch1 MB model makes it highly amenable to CRISPR-based genome editing screens to identify genes required for SHH MB tumor formation in vivo, and here we identify the grk3 kinase as one such target.

cancer biology↗

bioRxiv2024

MicroRNAs and mRNA Regulatory Network of Parenchymal Hematoma after Endovascular Mechanical Reperfusion for Acute Ischemic Stroke in Rat

Hemorrhagic transformation after endovascular thrombectomy predicts poor outcomes in acute ischemic stroke with large vessel occlusion. The roles of microRNAs in the pathogenesis of parenchymal hematoma (PH) are still unclear. This study aims to investigate the microRNA and mRNA regulatory network associated with PH after mechanical reperfusion in the animal stroke model and oxygen-glucose deprivation/reoxygenation (OGD/R) model. Twenty-five microRNAs were assessed in the reperfusion-induced hemorrhage model in rats with hyperglycemic conditions receiving 5-hour middle cerebral artery occlusion. Thirteen down-regulated microRNAs (miRNA-29a-5p, miRNA-29c-3p, miRNA-126a-5p, miRNA-132-3p, miRNA-136-3p, miRNA-142-3p, miRNA-153-5p, miRNA-218a-5p, miRNA-219a-2-3p, miRNA-369-5p, miRNA-376a-5p, miRNA-376b-5p, miRNA-383-5p) and one up-regulated microRNA (miRNA-195-3p) were found in rat peri-infarct with PH. Ten of these 14 PH-related microRNAs were significantly differentially expressed in at least two of five models of neuron, astrocyte, microglia, BMEC, and pericyte after OGD/R, consistent with the animal model results. Thirty-one predicted hub target genes were significantly differentially expressed in rat peri-infarct with PH. Forty-nine microRNA-mRNA regulatory axes of PH were revealed, which were related to the mechanisms of oxidative stress, apoptosis, immune, and inflammation. Simultaneously differentially expressed microRNAs and related genes in several cells of the neurovascular unit may serve as valuable targets for PH after endovascular thrombectomy in acute ischemic stroke.

neuroscience↗

bioRxiv2024

The Mechanism Insight into Bacterial Degradation of Pentachlorobiphenyl

Bacterial degradation mechanism for high chlorinated pentachlorobiphenyl (PentaCB) with worse biodegradability has not been fully elucidated, which could limit the full remediation of PCBs-combined pollution. In this research, using enzymatic screening method, a new PentaCB-degrading bacterium M. paraoxydans that has not been reported was obtained. The characteristic of its intracellular enzymes, proteome and metabolome variation during PentaCB degradation were investigated systematically. The results showed that PentaCB (PCB101, 1 mg/L) degradation rate could arrive 23.9% within 4 h till complete degradation within 12 h. The intracellular enzyme compound was optimally active at pH 6.0. The 12 up-regulated characterized proteins involved ABC transporter substrate-binding protein, translocase protein TatA and signal peptidase I (SPase I) indicated that functional proteins for PentaCB degradation were present both in the cytoplasm and outer surface of cytoplasmic membrane. There were also 5 differential metabolites strongly associated with above proteins in which the up-regulated 1, 2, 4-benzenetriol was enriched into the degradation pathways of benzoate, chlorocyclohexane, chlorobenzene and aminobenzoate. Bacterial degradation of PentaCB necessitates transmembrane transport, energy consumption, protein export, biofilm formation and quorum sensing. These findings hold significant theory and application value for PCBs biodegradation.

microbiology↗

bioRxiv2024

Targeted LNPs deliver mRNA encoding IL-15 superagonists to balance efficacy and toxicity in cancer therapy

Interleukin-15 (IL-15) emerges as a promising immunotherapeutic candidate in oncology because of its pivotal role in modulating both innate and adaptive immunity. However, the therapeutic utility remains concern due to the unexpected toxicity. We propose here that the mRNA lipid nanoparticle (mRNA-LNP) system can balance the issue through targeted delivery to increase IL-15 concentration in the tumor area and reduce leakage into the circulation. Utilizing the Structure-driven TARgeting (STAR) platform, we acquired intellectual property LNP vectors for effective and selective mRNA delivery to local (LNPLocal) and to pulmonary (LNPLung). Then the promising IL-15 superagonists mRNAs were obtained through structural optimization and sequence screening, showing better activity compared with benchmarker N-803. Subsequently, the anti-tumor efficacy of IL-15 superagonists mRNAs were evaluated by intratumoural (i.t.) injection and intravenous (i.v.) injection via LNPLocal and LNPLung, respectively. As a result, such superagonists exhibited better anti-tumor activity, less systematic exposure, and less cytokine related risks than N-803. We finally verified the selective delivery and well tolerability of LNPLung in non-human primates (NHPs), confirming the potential for clinical application. This finding may open up new possibilities for the treatment of lung cancers and lung metastasis cancers.

bioengineering↗

bioRxiv2024

Annotations of four high-quality indigenous chicken genomes identify more than one thousand missing genes in sub-telomeric regions with high G/C contents

BackgroundAlthough multiple chicken genomes have been assembled and annotated, the number of protein-coding genes in chicken genomes is still uncertain due to the low quality of these genome assemblies and limited resources used in gene annotations. ResultsTo fill the gap, we annotated our four recently assembled high-quality genomes of four indigenous chickens with distinct traits using a combination of RNA-seq- and homology-based approach. Our annotated genes in the four chickens recovered 51 of the 274 "missing" genes in birds in general and 36 of the 174 "missing" genes in chickens in particular. Intriguingly, based on deeply sequenced RNA-seq data collected in multiple tissues in each chicken breed, we found a total of 1,420 new protein-coding genes in the four chicken genomes, which were missed in the reference chicken genome annotations. These newly annotated genes (NAGs) tend to have high G/C contents and be located in sub-telomeric regions of almost all assembled chromosomes and some unplaced contigs. The NAGs showed tissue-specific expression and we were able to verify 39 (92.9%) of 42 randomly selected ones in various tissues of the four chicken breeds using RT-qPCR experiments. We found that most of the NAGs also are encoded in previously assembled chicken genomes. The NAGs form functional modules with homology-supported genes that are involved in many important biological pathways. We also identified numerous unique genes in each indigenous chicken genome that might be related to the unique traits of each breed. ConclusionThe ubiquitous presence of the NAGs in various chicken genomes indicate that they might play critical roles in chicken physiology. Counting these new genes, chicken genomes harbor more genes than originally thought.

bioinformatics↗

bioRxiv2024

Single-Nuclei RNA Sequencing Identifies Type C Low-Threshold Mechanoreceptors as Key Players in Paclitaxel-Induced Peripheral Neuropathy

Neuropathic pain triggered by chemotherapy poses a significant clinical challenge. Investigating cell type-specific alterations through single-cell transcriptome analysis holds promise in understanding symptom development and pathogenesis. In this study, we performed single nuclei RNA (snRNA) sequencing of dorsal root ganglions (DRG) to explore the molecular mechanism underlying paclitaxel-induced neuropathic pain. Mouse exposed to repeated paclitaxel doses developed persistent pain hypersensitivity lasting at least 21 days. The snRNA sequencing unveiled seven major cell types within DRGs, with neurons further subdivided into 12 distinct subclusters using known markers. Notably, type C low-threshold mechanoreceptors (C_LTMR) exhibited the most pronounced transcriptomic changes post-paclitaxel administration. Differential gene expression and Gene Ontology (GO) analysis highlighted suppressed potassium-related currents, microtubule transport, and mitochondrial functions in C_LTMR following paclitaxel treatment. Meanwhile, Gene Set Enrichment Analysis (GSEA) suggested increased Interleukin 17 production in C_LTMR after paclitaxel exposure. Pseudo-time analysis uncovered nine distinct states (state 1 to 9) of C_LTMR. State 1 exhibits higher prevalence in paclitaxel-treated mice and altered neurotransmission properties, likely contributing to paclitaxel-induced pain hypersensitivity. This comprehensive exploration sheds light on the molecular mechanisms driving paclitaxel-induced neuropathic pain, offering potential avenues for therapeutic intervention.

neuroscience↗

bioRxiv2023

One million years of solitude: the rapid evolution of de novo protein structure and complex

Recent studies have established that de novo genes, evolving from non-coding sequences, enhance protein diversity through a stepwise process. However, the pattern and rate of their structural evolution over time remain unclear. Here, we addressed these issues within a short evolutionary timeframe ([~]1 million years for 97% of rice de novo genes). We found that de novo genes evolve faster than gene duplicates in the intrinsic disordered regions (IDRs, such as random coils), secondary structural elements (such as -helix and {beta}-strand), hydrophobicity, and molecular recognition features (MoRFs). Specifically, we observed an 8-14% decay in random coils and IDR lengths per million years per protein, and a 2.3-6.5% increase in structured elements, hydrophobicity, and MoRFs. These patterns of structural evolution align with changes in amino acid composition over time. We also revealed significantly higher positive charges but smaller molecular weights for de novo proteins than duplicates. Tertiary structure predictions demonstrated that most de novo proteins, though not typically well-folded on their own, readily form low-energy and compact complexes with extensive residue contacts and conformational flexibility, suggesting "a faster-binding" scenario in de novo proteins to promote interaction. Our findings illuminate the rapid evolution of protein structure in the early life of de novo proteins in rice genome, originating from noncoding sequences, highlighting their quick transformation into active, complex-forming components within a remarkably short evolutionary timeframe.

evolutionary biology↗

bioRxiv2023

Emergence of a senescent and inflammatory pulmonary CD4+ T cell population prior to lung allograft failure

Lung transplantation is a life-saving therapy for end-stage pulmonary disease, but its long-term outlook is poor due to a high incidence of chronic lung allograft dysfunction (CLAD). CLAD results from alloimmune-mediated progressive fibrosis and culminates in death or the need for re-transplantation after a median of 6 years. Existing immunosuppression fails to prevent CLAD, suggesting the existence of alloimmune pathways resistant to these drugs. Here, we used mass cytometry to identify cell populations enriched in the bronchoalveolar lavage (BAL) of patients with subsequent allograft dysfunction. We show that CD4+CD57+PD1+ T cells emerge in stable lung transplant recipients in the first year post-transplant, conferring heightened risks for CLAD and death or re-transplantation. CD4+CD57+PD1+ T cells display features of senescence and secrete inflammatory cytokines. Cellular indexing by transcriptomes and epitopes (CITE-Seq) on BAL CD4+ T cells revealed the existence of 2 oligoclonal CD57+ subsets with putative cytotoxic and follicular helper functions. Finally, we observed that CD4+CD57+PD1+ T cells are associated with lung allograft fibrosis in a mouse model and in human explanted CLAD lungs, where they localize near airway epithelium and B cells. Together, our findings reveal the existence of an inflammatory T cell population that predicts future lung allograft dysfunction and may represent a rational therapeutic target in lung transplant recipients.

immunology↗