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The female reproductive tract (FRT) undergoes extensive remodeling during reproductive cycling. This recurrent remodeling and how it shapes organ-specific aging remains poorly explored. Using single-cell and spatial transcriptomics, we systematically characterized morphological and gene expression changes occurring in ovary, oviduct, uterus, cervix, and vagina at each phase of the mouse estrous cycle, during decidualization, and into aging. These analyses reveal that fibroblasts play central-and highly organ-specific-roles in FRT remodeling by orchestrating extracellular matrix (ECM) reorganization and inflammation. Our results suggest a model wherein recurrent FRT remodeling over reproductive lifespan drives the gradual, age-related development of fibrosis and chronic inflammation. This hypothesis was directly tested using chemical ablation of cycling, which reduced fibrotic accumulation during aging. Our atlas provides extensive detail into how estrus, pregnancy, and aging shape the organs of the female reproductive tract and reveals the unexpected cost of the recurrent remodeling required for reproduction.
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Envelhecimento , Genitália Feminina , Animais , Feminino , Camundongos , Gravidez , Genitália Feminina/citologia , Genitália Feminina/metabolismo , Inflamação/metabolismo , Útero/citologia , Vagina/citologia , Análise de Célula ÚnicaRESUMO
This year's Gairdner Foundation Award for Biomedical Research is awarded to John Dick for the discovery of leukemic stem cells and the hierarchical organization of acute myeloid leukemias. His work laid the foundation for the cancer stem cell model with numerous clinical implications for hematopoietic malignancies and solid tumors.
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Distinções e Prêmios , Pesquisa Biomédica , Leucemia Mieloide Aguda , Células-Tronco Neoplásicas , Humanos , Leucemia Mieloide Aguda/patologia , Células-Tronco Neoplásicas/patologiaRESUMO
Single-cell genomics technology has transformed our understanding of complex cellular systems. However, excessive cost and a lack of strategies for the purification of newly identified cell types impede their functional characterization and large-scale profiling. Here, we have generated high-content single-cell proteo-genomic reference maps of human blood and bone marrow that quantitatively link the expression of up to 197 surface markers to cellular identities and biological processes across all main hematopoietic cell types in healthy aging and leukemia. These reference maps enable the automatic design of cost-effective high-throughput cytometry schemes that outperform state-of-the-art approaches, accurately reflect complex topologies of cellular systems and permit the purification of precisely defined cell states. The systematic integration of cytometry and proteo-genomic data enables the functional capacities of precisely mapped cell states to be measured at the single-cell level. Our study serves as an accessible resource and paves the way for a data-driven era in cytometry.
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Células Sanguíneas/metabolismo , Células da Medula Óssea/metabolismo , Separação Celular , Citometria de Fluxo , Perfilação da Expressão Gênica , Proteoma , Proteômica , Análise de Célula Única , Transcriptoma , Fatores Etários , Células Sanguíneas/imunologia , Células Sanguíneas/patologia , Células da Medula Óssea/imunologia , Células da Medula Óssea/patologia , Células Cultivadas , Bases de Dados Genéticas , Envelhecimento Saudável/genética , Envelhecimento Saudável/imunologia , Envelhecimento Saudável/metabolismo , Humanos , Leucemia/genética , Leucemia/imunologia , Leucemia/metabolismo , Leucemia/patologia , RNA-Seq , Biologia de SistemasRESUMO
Mouse embryonic stem cells (ESCs) are maintained in a naive ground state of pluripotency in the presence of MEK and GSK3 inhibitors. Here, we show that ground-state ESCs express low Myc levels. Deletion of both c-myc and N-myc (dKO) or pharmacological inhibition of Myc activity strongly decreases transcription, splicing, and protein synthesis, leading to proliferation arrest. This process is reversible and occurs without affecting pluripotency, suggesting that Myc-depleted stem cells enter a state of dormancy similar to embryonic diapause. Indeed, c-Myc is depleted in diapaused blastocysts, and the differential expression signatures of dKO ESCs and diapaused epiblasts are remarkably similar. Following Myc inhibition, pre-implantation blastocysts enter biosynthetic dormancy but can progress through their normal developmental program after transfer into pseudo-pregnant recipients. Our study shows that Myc controls the biosynthetic machinery of stem cells without affecting their potency, thus regulating their entry and exit from the dormant state.
Assuntos
Células-Tronco Embrionárias/citologia , Genes myc , Proteínas Proto-Oncogênicas c-myc/genética , Animais , Blastocisto/metabolismo , Proliferação de Células , Embrião de Mamíferos/citologia , Embrião de Mamíferos/metabolismo , Células-Tronco Embrionárias/metabolismo , Feminino , Técnicas de Inativação de Genes , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Within the bone marrow, stem cells differentiate and give rise to diverse blood cell types and functions. Currently, hematopoietic progenitors are defined using surface markers combined with functional assays that are not directly linked with in vivo differentiation potential or gene regulatory mechanisms. Here, we comprehensively map myeloid progenitor subpopulations by transcriptional sorting of single cells from the bone marrow. We describe multiple progenitor subgroups, showing unexpected transcriptional priming toward seven differentiation fates but no progenitors with a mixed state. Transcriptional differentiation is correlated with combinations of known and previously undefined transcription factors, suggesting that the process is tightly regulated. Histone maps and knockout assays are consistent with early transcriptional priming, while traditional transplantation experiments suggest that in vivo priming may still allow for plasticity given strong perturbations. These data establish a reference model and general framework for studying hematopoiesis at single-cell resolution.
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Hematopoese , Células Progenitoras Mieloides/citologia , Células Progenitoras Mieloides/metabolismo , Análise de Célula Única , Transcriptoma , Animais , Transplante de Medula Óssea , Proteínas Estimuladoras de Ligação a CCAAT/genética , Técnicas de Inativação de Genes , Sequenciamento de Nucleotídeos em Larga Escala , Camundongos , Camundongos Endogâmicos C57BL , Análise de Sequência de RNA , Fatores de Transcrição/metabolismoRESUMO
Fiskin et al. (2021) developed a "multi-omics" approach that integrates phage-displayed single-domain antibodies ("nanobodies") with the assay for transposase-accessible chromatin (PHAGE-ATAC) to simultaneously determine protein expression, chromatin accessibility, and mitochondrial DNA mutations (for clonal tracing) in single cells.
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Bacteriófagos , Sequenciamento de Nucleotídeos em Larga Escala , Bacteriófagos/genética , Cromatina , Análise de Sequência de DNA , TransposasesRESUMO
Long noncoding RNAs (lncRNAs) are often expressed in a development-specific manner, yet little is known about their roles in lineage commitment. Here, we identified Braveheart (Bvht), a heart-associated lncRNA in mouse. Using multiple embryonic stem cell (ESC) differentiation strategies, we show that Bvht is required for progression of nascent mesoderm toward a cardiac fate. We find that Bvht is necessary for activation of a core cardiovascular gene network and functions upstream of mesoderm posterior 1 (MesP1), a master regulator of a common multipotent cardiovascular progenitor. We also show that Bvht interacts with SUZ12, a component of polycomb-repressive complex 2 (PRC2), during cardiomyocyte differentiation, suggesting that Bvht mediates epigenetic regulation of cardiac commitment. Finally, we demonstrate a role for Bvht in maintaining cardiac fate in neonatal cardiomyocytes. Together, our work provides evidence for a long noncoding RNA with critical roles in the establishment of the cardiovascular lineage during mammalian development.
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Diferenciação Celular , Células-Tronco Embrionárias/metabolismo , Miócitos Cardíacos/citologia , RNA Longo não Codificante , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Redes Reguladoras de Genes , Humanos , Mesoderma/citologia , Mesoderma/metabolismo , Camundongos , Miócitos Cardíacos/metabolismo , Complexo Repressor Polycomb 2/metabolismo , RatosRESUMO
PURPOSE OF REVIEW: To provide a comprehensive overview of the underlying genetic defects of pulmonary (vascular) diseases and novel treatment avenues. RECENT FINDINGS: Pulmonary arterial hypertension (PAH) is the prime example of a pulmonary vascular disease, which can be caused by genetic mutations in some patients. Germline mutations in the BMPR2 gene and further genes lead to vessel remodelling, increase of pulmonary vascular resistance and onset of heritable PAH. The PAH genes with the highest evidence and strategies for genetic testing and counselling have been assessed and evaluated in 2023 by international expert consortia. Moreover, first treatment options have just arisen targeting the molecular basis of PAH. SUMMARY: Apart from PAH, this review touches on the underlying genetic causes of further lung diseases including alpha 1 antitrypsin deficiency, cystic fibrosis, familial pulmonary fibrosis and lymphangioleiomyomatosis. We point out the main disease genes, the underlying pathomechanisms and novel therapies trying not only to relieve symptoms but to treat the molecular causes of the diseases.
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Testes Genéticos , Humanos , Deficiência de alfa 1-Antitripsina/genética , Deficiência de alfa 1-Antitripsina/complicações , Fibrose Cística/genética , Fibrose Cística/fisiopatologia , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Linfangioleiomiomatose/genética , Linfangioleiomiomatose/fisiopatologia , Hipertensão Pulmonar/genética , Hipertensão Arterial Pulmonar/genética , Hipertensão Arterial Pulmonar/fisiopatologia , Predisposição Genética para Doença , MutaçãoRESUMO
Aberrant activity of the SUMOylation pathway has been associated with MYC overexpression and poor prognosis in aggressive B-cell lymphoma (BCL) and other malignancies. Recently developed small-molecule inhibitors of SUMOylation (SUMOi) target the heterodimeric E1 SUMO activation complex (SAE1/UBA2). Here, we report that activated MYC signaling is an actionable molecular vulnerability in vitro and in a preclinical murine in vivo model of MYC-driven BCL. While SUMOi conferred direct effects on MYC-driven lymphoma cells, SUMO inhibition also resulted in substantial remodeling of various subsets of the innate and specific immunity in vivo. Specifically, SUMOi increased the number of memory B cells as well as cytotoxic and memory T cells, subsets that are attributed a key role within a coordinated anti-tumor immune response. In summary, our data constitute pharmacologic SUMOi as a powerful therapy in a subset of BCL causing massive remodeling of the normal B-cell and T-cell compartment.
Assuntos
Linfoma de Células B , Linfoma , Humanos , Camundongos , Animais , Proteínas Proto-Oncogênicas c-myc/metabolismo , Transdução de Sinais , Linfoma/tratamento farmacológico , Linfoma de Células B/tratamento farmacológico , Biomarcadores , Enzimas Ativadoras de Ubiquitina/metabolismoRESUMO
We present single molecule studies demonstrating the capabilities of the FRET-PAINT method to detect secondary structures that would be challenging to detect with alternative methods, particularly single molecule FRET (smFRET). Instead of relying on the change in end-to-end separation as in smFRET, we use the change in accessibility to a small probe as the criterion for secondary structure formation and relative stability. As a model system, we study G-triplex formation by human telomeric repeat sequences in different structural contexts.
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PURPOSE OF REVIEW: The bone marrow is home to hematopoietic stem cells responsible for lifelong blood production, alongside mesenchymal stem cells required for skeletal regeneration. In the bone marrow, a unique combination of signals derived from a multitude of cell types results in the establishment of so-called niches that regulate stem-cell maintenance and differentiation. Recently, single-cell and spatially resolved transcriptomics technologies have been utilized to characterize the murine bone marrow microenvironment during homeostasis, stress and upon cancer-induced remodeling. In this review, we summarize the major findings of these studies. RECENT FINDINGS: Single-cell technologies applied to bone marrow provided the first systematic and label-free identification of bone marrow cell types, enabled their molecular and spatial characterization, and clarified the cellular sources of key prohematopoietic factors. Large transcriptional heterogeneity and novel subpopulations were observed in compartments previously thought to be homogenous. For example, Lepr Cxcl12-abundant reticular cells were shown to constitute the major source of prohematopoietic factors, but consist of subpopulations differing in their adipogenic versus osteogenic priming, morphology and localization. These subpopulations were suggested to act as professional cytokine secreting cells, thereby establishing distinct bone marrow niches. SUMMARY: Single-cell and spatially resolved transcriptomics approaches have clarified the molecular identity and localization of bone marrow-resident cell types, paving the road for a deeper exploration of bone marrow niches in the mouse and humans.
Assuntos
Células da Medula Óssea/fisiologia , Perfilação da Expressão Gênica/métodos , Células-Tronco Hematopoéticas/fisiologia , Análise de Célula Única/métodos , Animais , Células da Medula Óssea/citologia , Microambiente Celular/fisiologia , Células-Tronco Hematopoéticas/citologia , HumanosRESUMO
In the bone marrow, endothelial cells are a major component of the hematopoietic stem cell vascular niche and are a first line of defense against inflammatory stress and infection. The primary response of an organism to infection involves the synthesis of immune-modulatory cytokines, including interferon alpha. In the bone marrow, interferon alpha induces rapid cell cycle entry of hematopoietic stem cells in vivo However, the effect of interferon alpha on bone marrow endothelial cells has not been described. Here, we demonstrate that acute interferon alpha treatment leads to rapid stimulation of bone marrow endothelial cells in vivo, resulting in increased bone marrow vascularity and vascular leakage. We find that activation of bone marrow endothelial cells involves the expression of key inflammatory and endothelial cell-stimulatory markers. This interferon alpha-mediated activation of bone marrow endothelial cells is dependent in part on vascular endothelial growth factor signaling in bone marrow hematopoietic cell types, including hematopoietic stem cells. Thus, this implies a role for hematopoietic stem cells in remodeling of the bone marrow niche in vivo following inflammatory stress. These data increase our current understanding of the relationship between hematopoietic stem cells and the bone marrow niche under inflammatory stress and also clarify the response of bone marrow niche endothelial cells to acute interferon alpha treatment in vivo.
Assuntos
Medula Óssea/metabolismo , Células Endoteliais/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Interferon-alfa/metabolismo , Nicho de Células-Tronco , Animais , Biomarcadores , Medula Óssea/irrigação sanguínea , Células da Medula Óssea/metabolismo , Permeabilidade Capilar , Proliferação de Células , Microambiente Celular , Feminino , Hematopoese , Células-Tronco Hematopoéticas/citologia , Imunofenotipagem , Interferon-alfa/genética , Interferon-alfa/farmacologia , Camundongos , Camundongos Knockout , Modelos Biológicos , Neovascularização Fisiológica , Fenótipo , Poli I-C/farmacologia , Transdução de Sinais/efeitos dos fármacos , Estresse Fisiológico , Fator A de Crescimento do Endotélio Vascular/biossínteseRESUMO
The use of single crystals has been fundamental to the development of semiconductor microelectronics and solid-state science. Whether based on inorganic or organic materials, the devices that show the highest performance rely on single-crystal interfaces, with their nearly perfect translational symmetry and exceptionally high chemical purity. Attention has recently been focused on developing simple ways of producing electronic devices by means of printing technologies. 'Printed electronics' is being explored for the manufacture of large-area and flexible electronic devices by the patterned application of functional inks containing soluble or dispersed semiconducting materials. However, because of the strong self-organizing tendency of the deposited materials, the production of semiconducting thin films of high crystallinity (indispensable for realizing high carrier mobility) may be incompatible with conventional printing processes. Here we develop a method that combines the technique of antisolvent crystallization with inkjet printing to produce organic semiconducting thin films of high crystallinity. Specifically, we show that mixing fine droplets of an antisolvent and a solution of an active semiconducting component within a confined area on an amorphous substrate can trigger the controlled formation of exceptionally uniform single-crystal or polycrystalline thin films that grow at the liquid-air interfaces. Using this approach, we have printed single crystals of the organic semiconductor 2,7-dioctyl[1]benzothieno[3,2-b][1]benzothiophene (C(8)-BTBT) (ref. 15), yielding thin-film transistors with average carrier mobilities as high as 16.4 cm(2) V(-1) s(-1). This printing technique constitutes a major step towards the use of high-performance single-crystal semiconductor devices for large-area and flexible electronics applications.
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Cristalização , Eletrônica/instrumentação , Eletrônica/métodos , Impressão/métodos , Semicondutores , Anisotropia , Plásticos/química , Solventes , Síncrotrons , Tiofenos/química , Transistores Eletrônicos , Difração de Raios XRESUMO
We introduce a new hyaluronidase-responsive amphiphilic block copolymer system, based on hyaluronic acid (HYA) and polycaprolactone (PCL), that can be assembled into polymersomes by an inversed solvent shift method. By exploiting the triggered release of encapsulated dye molecules, these HYA-block-PCL polymersomes lend themselves as an autonomous sensing system for the detection of the presence of hyaluronidase, which is produced among others by the pathogenic bacterium Staphylococcus aureus. The synthesis of the enzyme-responsive HYA-block-PCL block copolymers was carried out by copper-catalyzed Huisgen 1,3-dipolar cycloaddition of ω-azide-terminated PCL and ω-alkyne-functionalized HYA. The structure of the HYA-block-PCL assemblies and their enzyme-triggered degradation and concomitant cargo release were investigated by dynamic light scattering, fluorescence spectroscopy, confocal laser-scanning microscopy, scanning and transmission electron, and atomic force microscopy. As shown, a wide range of reporter dye molecules as well as antimicrobials can be encapsulated into the vesicles during formation and are released upon the addition of hyaluronidase.
Assuntos
Proteínas de Bactérias/química , Ácido Hialurônico/análogos & derivados , Ácido Hialurônico/química , Hialuronoglucosaminidase/química , Poliésteres/química , Ensaios Enzimáticos , Corantes Fluorescentes/química , Cinética , Nanocápsulas/química , Tamanho da Partícula , Staphylococcus aureus/enzimologiaRESUMO
Therapeutic gene transfer by replication-defective viral vectors or, for cancer treatment, by replication-competent oncolytic viruses shows high promise for treatment of major diseases. To ensure safety, timing or dosing in patients, external control of therapeutic gene expression is desirable or even required. In this study, we explored the potential of artificial aptazymes, ligand-dependent self-cleaving ribozymes, as an innovative tool for regulation of therapeutic gene expression. Importantly, aptazymes act on RNA intrinsically, independent of regulatory protein-nucleic acid interactions and stoichiometry, are non-immunogenic and of small size. These are key advantages compared with the widely used inducible promoters, which were also reported to lose regulation at high copy numbers, e.g. after replication of oncolytic viruses. We characterized aptazymes in therapeutic gene transfer utilizing adenovectors (AdVs), adeno-associated vectors (AAVs) and oncolytic adenoviruses (OAds), which are all in advanced clinical testing. Our results show similar aptazyme-mediated regulation of gene expression by plasmids, AdVs, AAVs and OAds. Insertion into the 5'-, 3'- or both untranslated regions of several transgenes resulted in ligand-responsive gene expression. Notably, aptazyme regulation was retained during OAd replication and spread. In conclusion, our study demonstrates the fidelity of aptazymes in viral vectors and oncolytic viruses and highlights the potency of riboswitches for medical applications.
Assuntos
Adenoviridae/genética , Regulação da Expressão Gênica , Vírus Oncolíticos/genética , RNA Catalítico/genética , Riboswitch , Adenoviridae/fisiologia , Linhagem Celular Tumoral , Vírus Defeituosos/genética , Dependovirus/genética , Vetores Genéticos , Genoma Viral , Humanos , RNA Catalítico/metabolismo , Transdução Genética , Transgenes , Regiões não Traduzidas , Replicação ViralRESUMO
Hematopoietic stem and progenitor cells (HSPCs) are known to respond to acute inflammation; however, little is understood about the dynamics and heterogeneity of these stress responses in HSPCs. Here, we performed single-cell sequencing during the sensing, response, and recovery phases of the inflammatory response of HSPCs to treatment (a total of 10,046 cells from four time points spanning the first 72 h of response) with the pro-inflammatory cytokine IFNα to investigate the HSPCs' dynamic changes during acute inflammation. We developed the essential novel computational approaches to process and analyze the resulting single-cell time series dataset. This includes an unbiased cell type annotation and abundance analysis post inflammation, tools for identification of global and cell type-specific responding genes, and a semi-supervised linear regression approach for response pseudotime reconstruction. We discovered a variety of different gene responses of the HSPCs to the treatment. Interestingly, we were able to associate a global reduced myeloid differentiation program and a locally enhanced pyroptosis activity with reduced myeloid progenitor and differentiated cells after IFNα treatment. Altogether, the single-cell time series analyses have allowed us to unbiasedly study the heterogeneous and dynamic impact of IFNα on the HSPCs.
Assuntos
Hematopoese , Células-Tronco Hematopoéticas , Humanos , Fatores de Tempo , Diferenciação Celular/genética , Hematopoese/genética , Inflamação/metabolismoRESUMO
For many diseases there are delays in diagnosis due to a lack of objective biomarkers for disease onset. Here, in 41,931 individuals from the United Kingdom Biobank Pharma Proteomics Project, we integrated measurements of ~3,000 plasma proteins with clinical information to derive sparse prediction models for the 10-year incidence of 218 common and rare diseases (81-6,038 cases). We then compared prediction models developed using proteomic data with models developed using either basic clinical information alone or clinical information combined with data from 37 clinical assays. The predictive performance of sparse models including as few as 5 to 20 proteins was superior to the performance of models developed using basic clinical information for 67 pathologically diverse diseases (median delta C-index = 0.07; range = 0.02-0.31). Sparse protein models further outperformed models developed using basic information combined with clinical assay data for 52 diseases, including multiple myeloma, non-Hodgkin lymphoma, motor neuron disease, pulmonary fibrosis and dilated cardiomyopathy. For multiple myeloma, single-cell RNA sequencing from bone marrow in newly diagnosed patients showed that four of the five predictor proteins were expressed specifically in plasma cells, consistent with the strong predictive power of these proteins. External replication of sparse protein models in the EPIC-Norfolk study showed good generalizability for prediction of the six diseases tested. These findings show that sparse plasma protein signatures, including both disease-specific proteins and protein predictors shared across several diseases, offer clinically useful prediction of common and rare diseases.
Assuntos
Proteômica , Doenças Raras , Humanos , Proteômica/métodos , Doenças Raras/sangue , Doenças Raras/diagnóstico , Doenças Raras/genética , Reino Unido/epidemiologia , Feminino , Masculino , Biomarcadores/sangue , Proteínas Sanguíneas/metabolismo , Pessoa de Meia-Idade , Idoso , Adulto , Medição de RiscoRESUMO
Third-generation chimeric antigen receptor T cells (CARTs) for relapsed or refractory (r/r) chronic lymphocytic leukemia (CLL) may improve efficacy compared to second-generation CARTs due to their enhanced CAR design. We performed the first phase 1/2 investigator-initiated trial evaluating escalating doses of third-generation CARTs (HD-CAR-1) targeting CD19 in patients with r/r CLL and B-cell lymphoma. CLL eligibility criteria were failure to two therapy lines including at least one pathway inhibitor and/or allogeneic hematopoietic cell transplantation. Nine heavily pretreated patients received HD-CAR-1 at dose levels ranging from 1 × 106 to 200 × 106 CART/m2. In-house HD-CAR-1 manufacturing was successful for all patients. While neurotoxicity was absent, one case of grade 3 cytokine release syndrome was observed. By day 90, six patients (67%) attained a CR, five of these (83%) with undetectable MRD. With a median follow-up of 27 months, 2-year PFS and OS were 30% and 69%, respectively. HD-CAR-1 products of responders contained significantly more CD4 + T cells compared to non-responders. In non-responders, a strong enrichment of effector memory-like CD8 + T cells with high expression of CD39 and/or CD197 was observed. HD-CAR-1 demonstrated encouraging efficacy and exceptionally low treatment-specific toxicity, presenting new treatment options for patients with r/r CLL. Trial registration: #NCT03676504.
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The IL-6-gp130-STAT3 signaling axis is a major regulator of inflammation. Activating mutations in the gene encoding gp130 and germline gain-of-function mutations in STAT3 (STAT3GOF) are associated with multi-organ autoimmunity, severe morbidity, and adverse prognosis. To dissect crucial cellular subsets and disease biology involved in activated gp130 signaling, the gp130-JAK-STAT3 axis was constitutively activated using a transgene, L-gp130, specifically targeted to T cells. Activating gp130 signaling in T cells in vivo resulted in fatal, early onset, multi-organ autoimmunity in mice that resembled human STAT3GOF disease. Female mice had more rapid disease progression than male mice. On a cellular level, gp130 signaling induced the activation and effector cell differentiation of T cells, promoted the expansion of T helper type 17 (TH17) cells, and impaired the activity of regulatory T cells. Transcriptomic profiling of CD4+ and CD8+ T cells from these mice revealed commonly dysregulated genes and a gene signature that, when applied to human transcriptomic data, improved the segregation of patients with transcriptionally diverse STAT3GOF mutations from healthy controls. The findings demonstrate that increased gp130-STAT3 signaling leads to TH17-driven autoimmunity that phenotypically resembles human STAT3GOF disease.