RESUMEN
The enigmatic eosinophil has emerged as an exciting component of the immune system, involved in a plethora of homeostatic and inflammatory responses. Substantial progress has been achieved through experimental systems manipulating eosinophils in vivo, initially in mice and more recently in humans. Researchers using eosinophil knockout mice have identified a contributory role for eosinophils in basal and inflammatory processes and protective immunity. Primarily fueled by the purported proinflammatory role of eosinophils in eosinophil-associated diseases, a series of anti-eosinophil therapeutics have emerged as a new class of drugs. These agents, which dramatically deplete eosinophils, provide a valuable opportunity to characterize the consequences of eosinophil knockout humans. Herein, we comparatively describe mouse and human eosinophil knockouts. We put forth the view that human eosinophils negatively contribute to a variety of diseases and, unlike mouse eosinophils, do not yet have an identified role in physiological health; thus, clarifying all roles of eosinophils remains an ongoing pursuit.
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Eosinófilos , Preparaciones Farmacéuticas , Animales , Terapia Biológica , Humanos , Ratones , Ratones NoqueadosRESUMEN
The very-low-density lipoprotein receptor (VLDLR) comprises eight LDLR type A (LA) domains and supports entry of distantly related alphaviruses, including Eastern equine encephalitis virus (EEEV) and Semliki Forest virus (SFV). Here, by resolving multiple cryo-electron microscopy structures of EEEV-VLDLR complexes and performing mutagenesis and functional studies, we show that EEEV uses multiple sites (E1/E2 cleft and E2 A domain) to engage more than one LA domain simultaneously. However, no single LA domain is necessary or sufficient to support efficient EEEV infection. Whereas all EEEV strains show conservation of two VLDLR-binding sites, the EEEV PE-6 strain and a few other EEE complex members feature a single amino acid substitution that enables binding of LA domains to an additional site on the E2 B domain. These structural and functional analyses informed the design of a minimal VLDLR decoy receptor that neutralizes EEEV infection and protects mice from lethal challenge.
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Microscopía por Crioelectrón , Virus de la Encefalitis Equina del Este , Encefalomielitis Equina , Receptores de LDL , Animales , Ratones , Alphavirus/fisiología , Virus de la Encefalitis Equina del Este/fisiología , Virus de la Encefalitis Equina del Este/ultraestructura , Encefalomielitis Equina/metabolismo , Caballos , Unión Proteica , Receptores de LDL/ultraestructuraRESUMEN
Streptococcus anginosus (S. anginosus) was enriched in the gastric mucosa of patients with gastric cancer (GC). Here, we show that S. anginosus colonized the mouse stomach and induced acute gastritis. S. anginosus infection spontaneously induced progressive chronic gastritis, parietal cell atrophy, mucinous metaplasia, and dysplasia in conventional mice, and the findings were confirmed in germ-free mice. In addition, S. anginosus accelerated GC progression in carcinogen-induced gastric tumorigenesis and YTN16 GC cell allografts. Consistently, S. anginosus disrupted gastric barrier function, promoted cell proliferation, and inhibited apoptosis. Mechanistically, we identified an S. anginosus surface protein, TMPC, that interacts with Annexin A2 (ANXA2) receptor on gastric epithelial cells. Interaction of TMPC with ANXA2 mediated attachment and colonization of S. anginosus and induced mitogen-activated protein kinase (MAPK) activation. ANXA2 knockout abrogated the induction of MAPK by S. anginosus. Thus, this study reveals S. anginosus as a pathogen that promotes gastric tumorigenesis via direct interactions with gastric epithelial cells in the TMPC-ANXA2-MAPK axis.
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Gastritis , Neoplasias Gástricas , Infecciones Estreptocócicas , Streptococcus anginosus , Animales , Humanos , Ratones , Atrofia/patología , Carcinogénesis , Transformación Celular Neoplásica , Mucosa Gástrica , Gastritis/patología , Inflamación/patología , Proteínas Quinasas Activadas por Mitógenos , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/patología , Streptococcus anginosus/fisiología , Infecciones Estreptocócicas/patologíaRESUMEN
Respiratory infections cause significant morbidity and mortality, yet it is unclear why some individuals succumb to severe disease. In patients hospitalized with avian A(H7N9) influenza, we investigated early drivers underpinning fatal disease. Transcriptomics strongly linked oleoyl-acyl-carrier-protein (ACP) hydrolase (OLAH), an enzyme mediating fatty acid production, with fatal A(H7N9) early after hospital admission, persisting until death. Recovered patients had low OLAH expression throughout hospitalization. High OLAH levels were also detected in patients hospitalized with life-threatening seasonal influenza, COVID-19, respiratory syncytial virus (RSV), and multisystem inflammatory syndrome in children (MIS-C) but not during mild disease. In olah-/- mice, lethal influenza infection led to survival and mild disease as well as reduced lung viral loads, tissue damage, infection-driven pulmonary cell infiltration, and inflammation. This was underpinned by differential lipid droplet dynamics as well as reduced viral replication and virus-induced inflammation in macrophages. Supplementation of oleic acid, the main product of OLAH, increased influenza replication in macrophages and their inflammatory potential. Our findings define how the expression of OLAH drives life-threatening viral disease.
RESUMEN
Mycobacterium tuberculosis (Mtb) causes 1.6 million deaths annually. Active tuberculosis correlates with a neutrophil-driven type I interferon (IFN) signature, but the cellular mechanisms underlying tuberculosis pathogenesis remain poorly understood. We found that interstitial macrophages (IMs) and plasmacytoid dendritic cells (pDCs) are dominant producers of type I IFN during Mtb infection in mice and non-human primates, and pDCs localize near human Mtb granulomas. Depletion of pDCs reduces Mtb burdens, implicating pDCs in tuberculosis pathogenesis. During IFN-driven disease, we observe abundant DNA-containing neutrophil extracellular traps (NETs) described to activate pDCs. Cell-type-specific disruption of the type I IFN receptor suggests that IFNs act on IMs to inhibit Mtb control. Single-cell RNA sequencing (scRNA-seq) indicates that type I IFN-responsive cells are defective in their response to IFNγ, a cytokine critical for Mtb control. We propose that pDC-derived type I IFNs act on IMs to permit bacterial replication, driving further neutrophil recruitment and active tuberculosis disease.
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Interferón Tipo I , Tuberculosis , Humanos , Ratones , Animales , Macrófagos/microbiología , Citocinas , Neutrófilos , Células DendríticasRESUMEN
Transgenerational epigenetic inheritance in mammals remains a debated subject. Here, we demonstrate that DNA methylation of promoter-associated CpG islands (CGIs) can be transmitted from parents to their offspring in mice. We generated DNA methylation-edited mouse embryonic stem cells (ESCs), in which CGIs of two metabolism-related genes, the Ankyrin repeat domain 26 and the low-density lipoprotein receptor, were specifically methylated and silenced. DNA methylation-edited mice generated by microinjection of the methylated ESCs exhibited abnormal metabolic phenotypes. Acquired methylation of the targeted CGI and the phenotypic traits were maintained and transmitted across multiple generations. The heritable CGI methylation was subjected to reprogramming in parental PGCs and subsequently reestablished in the next generation at post-implantation stages. These observations provide a concrete step toward demonstrating transgenerational epigenetic inheritance in mammals, which may have implications in our understanding of evolutionary biology as well as the etiology, diagnosis, and prevention of non-genetically inherited human diseases.
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Metilación de ADN , Epigénesis Genética , Ratones , Humanos , Animales , Islas de CpG , Patrón de Herencia , Mamíferos/genéticaRESUMEN
The large number of spike substitutions in Omicron lineage variants (BA.1, BA.1.1., and BA.2) could jeopardize the efficacy of SARS-CoV-2 vaccines. We evaluated in mice the protective efficacy of the Moderna mRNA-1273 vaccine against BA.1 before or after boosting. Whereas two doses of mRNA-1273 vaccine induced high levels of neutralizing antibodies against historical WA1/2020 strains, lower levels against BA.1 were associated with breakthrough infection and inflammation in the lungs. A primary vaccination series with mRNA-1273.529, an Omicron-matched vaccine, potently neutralized BA.1 but inhibited historical or other SARS-CoV-2 variants less effectively. However, boosting with either mRNA-1273 or mRNA-1273.529 vaccines increased neutralizing titers and protection against BA.1 and BA.2 infection. Nonetheless, the neutralizing antibody titers were higher, and lung viral burden and cytokines were slightly lower in mice boosted with mRNA-1273.529 and challenged with BA.1. Thus, boosting with mRNA-1273 or mRNA-1273.529 enhances protection against Omicron infection with limited differences in efficacy measured.
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COVID-19 , SARS-CoV-2 , Vacuna nCoV-2019 mRNA-1273 , Animales , Anticuerpos Neutralizantes , Anticuerpos Antivirales , COVID-19/prevención & control , Vacunas contra la COVID-19 , Humanos , Ratones , SARS-CoV-2/genética , Vacunación , Vacunas Sintéticas , Vacunas de ARNmRESUMEN
Great progress has been made in understanding gut microbiomes' products and their effects on health and disease. Less attention, however, has been given to the inputs that gut bacteria consume. Here, we quantitatively examine inputs and outputs of the mouse gut microbiome, using isotope tracing. The main input to microbial carbohydrate fermentation is dietary fiber and to branched-chain fatty acids and aromatic metabolites is dietary protein. In addition, circulating host lactate, 3-hydroxybutyrate, and urea (but not glucose or amino acids) feed the gut microbiome. To determine the nutrient preferences across bacteria, we traced into genus-specific bacterial protein sequences. We found systematic differences in nutrient use: most genera in the phylum Firmicutes prefer dietary protein, Bacteroides dietary fiber, and Akkermansia circulating host lactate. Such preferences correlate with microbiome composition changes in response to dietary modifications. Thus, diet shapes the microbiome by promoting the growth of bacteria that preferentially use the ingested nutrients.
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Microbioma Gastrointestinal , Animales , Bacterias , Dieta , Fibras de la Dieta/metabolismo , Proteínas en la Dieta/metabolismo , Lactatos/metabolismo , Ratones , NutrientesRESUMEN
Plant fibers in byproduct streams produced by non-harsh food processing methods represent biorepositories of diverse, naturally occurring, and physiologically active biomolecules. To demonstrate one approach for their characterization, mass spectrometry of intestinal contents from gnotobiotic mice, plus in vitro studies, revealed liberation of N-methylserotonin from orange fibers by human gut microbiota members including Bacteroides ovatus. Functional genomic analyses of B. ovatus strains grown under permissive and non-permissive N-methylserotonin "mining" conditions revealed polysaccharide utilization loci that target pectins whose expression correlate with strain-specific liberation of this compound. N-methylserotonin, orally administered to germ-free mice, reduced adiposity, altered liver glycogenesis, shortened gut transit time, and changed expression of genes that regulate circadian rhythm in the liver and colon. In human studies, dose-dependent, orange-fiber-specific fecal accumulation of N-methylserotonin positively correlated with levels of microbiome genes encoding enzymes that digest pectic glycans. Identifying this type of microbial mining activity has potential therapeutic implications.
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Citrus sinensis , Microbioma Gastrointestinal , Animales , Citrus sinensis/metabolismo , Fibras de la Dieta , Microbioma Gastrointestinal/fisiología , Vida Libre de Gérmenes , Humanos , Ratones , Pectinas/metabolismo , Polisacáridos/metabolismo , Serotonina/análogos & derivadosRESUMEN
We developed a miniaturized two-photon microscope (MINI2P) for fast, high-resolution, multiplane calcium imaging of over 1,000 neurons at a time in freely moving mice. With a microscope weight below 3 g and a highly flexible connection cable, MINI2P allowed stable imaging with no impediment of behavior in a variety of assays compared to untethered, unimplanted animals. The improved cell yield was achieved through a optical system design featuring an enlarged field of view (FOV) and a microtunable lens with increased z-scanning range and speed that allows fast and stable imaging of multiple interleaved planes, as well as 3D functional imaging. Successive imaging across multiple, adjacent FOVs enabled recordings from more than 10,000 neurons in the same animal. Large-scale proof-of-principle data were obtained from cell populations in visual cortex, medial entorhinal cortex, and hippocampus, revealing spatial tuning of cells in all areas.
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Calcio , Corteza Visual , Animales , Corteza Entorrinal , Hipocampo , Ratones , Microscopía , Neuronas/fisiologíaRESUMEN
Alphaviruses are emerging, mosquito-transmitted pathogens that cause musculoskeletal and neurological disease in humans. Although neutralizing antibodies that inhibit individual alphaviruses have been described, broadly reactive antibodies that protect against both arthritogenic and encephalitic alphaviruses have not been reported. Here, we identify DC2.112 and DC2.315, two pan-protective yet poorly neutralizing human monoclonal antibodies (mAbs) that avidly bind to viral antigen on the surface of cells infected with arthritogenic and encephalitic alphaviruses. These mAbs engage a conserved epitope in domain II of the E1 protein proximal to and within the fusion peptide. Treatment with DC2.112 or DC2.315 protects mice against infection by both arthritogenic (chikungunya and Mayaro) and encephalitic (Venezuelan, Eastern, and Western equine encephalitis) alphaviruses through multiple mechanisms, including inhibition of viral egress and monocyte-dependent Fc effector functions. These findings define a conserved epitope recognized by weakly neutralizing yet protective antibodies that could be targeted for pan-alphavirus immunotherapy and vaccine design.
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Alphavirus/inmunología , Anticuerpos Antivirales/inmunología , Secuencia Conservada/inmunología , Epítopos/inmunología , Proteínas Virales/inmunología , Infecciones por Alphavirus/inmunología , Infecciones por Alphavirus/virología , Secuencia de Aminoácidos , Animales , Anticuerpos Monoclonales/inmunología , Fiebre Chikungunya/inmunología , Fiebre Chikungunya/virología , Virus Chikungunya/inmunología , Chlorocebus aethiops , Mapeo Epitopo , Epítopos/química , Humanos , Masculino , Ratones Endogámicos C57BL , Modelos Biológicos , Monocitos/metabolismo , Células Vero , Proteínas Virales/química , Liberación del VirusRESUMEN
Every day we make decisions critical for adaptation and survival. We repeat actions with known consequences. But we also draw on loosely related events to infer and imagine the outcome of entirely novel choices. These inferential decisions are thought to engage a number of brain regions; however, the underlying neuronal computation remains unknown. Here, we use a multi-day cross-species approach in humans and mice to report the functional anatomy and neuronal computation underlying inferential decisions. We show that during successful inference, the mammalian brain uses a hippocampal prospective code to forecast temporally structured learned associations. Moreover, during resting behavior, coactivation of hippocampal cells in sharp-wave/ripples represent inferred relationships that include reward, thereby "joining-the-dots" between events that have not been observed together but lead to profitable outcomes. Computing mnemonic links in this manner may provide an important mechanism to build a cognitive map that stretches beyond direct experience, thus supporting flexible behavior.
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Toma de Decisiones/fisiología , Red Nerviosa/fisiología , Pensamiento/fisiología , Animales , Encéfalo/fisiología , Femenino , Hipocampo/metabolismo , Hipocampo/fisiología , Humanos , Masculino , Memoria/fisiología , Ratones , Ratones Endogámicos C57BL , Modelos Neurológicos , Neuronas/metabolismo , Neuronas/fisiología , Estudios Prospectivos , Adulto JovenRESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic with millions of human infections. One limitation to the evaluation of potential therapies and vaccines to inhibit SARS-CoV-2 infection and ameliorate disease is the lack of susceptible small animals in large numbers. Commercially available laboratory strains of mice are not readily infected by SARS-CoV-2 because of species-specific differences in their angiotensin-converting enzyme 2 (ACE2) receptors. Here, we transduced replication-defective adenoviruses encoding human ACE2 via intranasal administration into BALB/c mice and established receptor expression in lung tissues. hACE2-transduced mice were productively infected with SARS-CoV-2, and this resulted in high viral titers in the lung, lung pathology, and weight loss. Passive transfer of a neutralizing monoclonal antibody reduced viral burden in the lung and mitigated inflammation and weight loss. The development of an accessible mouse model of SARS-CoV-2 infection and pathogenesis will expedite the testing and deployment of therapeutics and vaccines.
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Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Neutralizantes/uso terapéutico , Anticuerpos Antivirales/uso terapéutico , Betacoronavirus/inmunología , Infecciones por Coronavirus/terapia , Modelos Animales de Enfermedad , Neumonía Viral/terapia , Enzima Convertidora de Angiotensina 2 , Animales , COVID-19 , Chlorocebus aethiops , Infecciones por Coronavirus/virología , Femenino , Células HEK293 , Humanos , Inmunización Pasiva/métodos , Pulmón/metabolismo , Pulmón/virología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Noqueados , Pandemias , Peptidil-Dipeptidasa A/genética , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/virología , SARS-CoV-2 , Transducción Genética , Células Vero , Carga Viral/inmunologíaRESUMEN
Recent large-scale collaborations are generating major surveys of cell types and connections in the mouse brain, collecting large amounts of data across modalities, spatial scales, and brain areas. Successful integration of these data requires a standard 3D reference atlas. Here, we present the Allen Mouse Brain Common Coordinate Framework (CCFv3) as such a resource. We constructed an average template brain at 10 µm voxel resolution by interpolating high resolution in-plane serial two-photon tomography images with 100 µm z-sampling from 1,675 young adult C57BL/6J mice. Then, using multimodal reference data, we parcellated the entire brain directly in 3D, labeling every voxel with a brain structure spanning 43 isocortical areas and their layers, 329 subcortical gray matter structures, 81 fiber tracts, and 8 ventricular structures. CCFv3 can be used to analyze, visualize, and integrate multimodal and multiscale datasets in 3D and is openly accessible (https://atlas.brain-map.org/).
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Encéfalo/anatomía & histología , Encéfalo/metabolismo , Encéfalo/fisiología , Animales , Atlas como Asunto , Mapeo Encefálico/métodos , Procesamiento de Imagen Asistido por Computador/métodos , Imagenología Tridimensional/métodos , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Working memory is a form of short-term memory that involves maintaining and updating task-relevant information toward goal-directed pursuits. Classical models posit persistent activity in prefrontal cortex (PFC) as a primary neural correlate, but emerging views suggest additional mechanisms may exist. We screened â¼200 genetically diverse mice on a working memory task and identified a genetic locus on chromosome 5 that contributes to a substantial proportion (17%) of the phenotypic variance. Within the locus, we identified a gene encoding an orphan G-protein-coupled receptor, Gpr12, which is sufficient to drive substantial and bidirectional changes in working memory. Molecular, cellular, and imaging studies revealed that Gpr12 enables high thalamus-PFC synchrony to support memory maintenance and choice accuracy. These findings identify an orphan receptor as a potent modifier of short-term memory and supplement classical PFC-based models with an emerging thalamus-centric framework for the mechanistic understanding of working memory.
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Memoria a Corto Plazo/fisiología , Receptores Acoplados a Proteínas G/genética , Tálamo/metabolismo , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Vías Nerviosas/fisiología , Neuronas/metabolismo , Neuronas/fisiología , Corteza Prefrontal/fisiología , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
Broadly neutralizing antibodies (bNAbs) represent a promising approach to prevent and treat HIV-1 infection. However, viral escape through mutation of the HIV-1 envelope glycoprotein (Env) limits clinical applications. Here we describe 1-18, a new VH1-46-encoded CD4 binding site (CD4bs) bNAb with outstanding breadth (97%) and potency (GeoMean IC50 = 0.048 µg/mL). Notably, 1-18 is not susceptible to typical CD4bs escape mutations and effectively overcomes HIV-1 resistance to other CD4bs bNAbs. Moreover, mutational antigenic profiling uncovered restricted pathways of HIV-1 escape. Of most promise for therapeutic use, even 1-18 alone fully suppressed viremia in HIV-1-infected humanized mice without selecting for resistant viral variants. A 2.5-Å cryo-EM structure of a 1-18-BG505SOSIP.664 Env complex revealed that these characteristics are likely facilitated by a heavy-chain insertion and increased inter-protomer contacts. The ability of 1-18 to effectively restrict HIV-1 escape pathways provides a new option to successfully prevent and treat HIV-1 infection.
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Anticuerpos ampliamente neutralizantes/inmunología , Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Sitios de Unión , Antígenos CD4/metabolismo , Células CHO , Estudios de Cohortes , Cricetulus , Epítopos/inmunología , Femenino , Células HEK293 , Infecciones por VIH/prevención & control , Infecciones por VIH/virología , Xenoinjertos , Humanos , Masculino , Ratones , Ratones Endogámicos NOD , Persona de Mediana Edad , Mutación , Unión Proteica/inmunología , Productos del Gen env del Virus de la Inmunodeficiencia Humana/genéticaRESUMEN
Rotavirus (RV) encounters intestinal epithelial cells amidst diverse microbiota, opening possibilities of microbes influencing RV infection. Although RV clearance typically requires adaptive immunity, we unintentionally generated RV-resistant immunodeficient mice, which, we hypothesized, reflected select microbes protecting against RV. Accordingly, such RV resistance was transferred by co-housing and fecal transplant. RV-protecting microbiota were interrogated by heat, filtration, and antimicrobial agents, followed by limiting dilution transplant to germ-free mice and microbiome analysis. This approach revealed that segmented filamentous bacteria (SFB) were sufficient to protect mice against RV infection and associated diarrhea. Such protection was independent of previously defined RV-impeding factors, including interferon, IL-17, and IL-22. Colonization of the ileum by SFB induced changes in host gene expression and accelerated epithelial cell turnover. Incubation of RV with SFB-containing feces reduced infectivity in vitro, suggesting direct neutralization of RV. Thus, independent of immune cells, SFB confer protection against certain enteric viral infections and associated diarrheal disease.
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Inmunidad Adaptativa/genética , Diarrea/microbiología , Mucosa Intestinal/microbiología , Infecciones por Rotavirus/microbiología , Animales , Antiinfecciosos/farmacología , Bacterias/genética , Bacterias/metabolismo , Diarrea/prevención & control , Diarrea/virología , Heces/microbiología , Regulación de la Expresión Génica/genética , Humanos , Íleon/microbiología , Íleon/patología , Íleon/virología , Interferones/genética , Interleucina-17/genética , Interleucinas/genética , Mucosa Intestinal/patología , Mucosa Intestinal/virología , Ratones , Microbiota/genética , Rotavirus/patogenicidad , Infecciones por Rotavirus/prevención & control , Infecciones por Rotavirus/virología , Interleucina-22RESUMEN
Modern genetic approaches are powerful in providing access to diverse cell types in the brain and facilitating the study of their function. Here, we report a large set of driver and reporter transgenic mouse lines, including 23 new driver lines targeting a variety of cortical and subcortical cell populations and 26 new reporter lines expressing an array of molecular tools. In particular, we describe the TIGRE2.0 transgenic platform and introduce Cre-dependent reporter lines that enable optical physiology, optogenetics, and sparse labeling of genetically defined cell populations. TIGRE2.0 reporters broke the barrier in transgene expression level of single-copy targeted-insertion transgenesis in a wide range of neuronal types, along with additional advantage of a simplified breeding strategy compared to our first-generation TIGRE lines. These novel transgenic lines greatly expand the repertoire of high-precision genetic tools available to effectively identify, monitor, and manipulate distinct cell types in the mouse brain.
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Encéfalo/metabolismo , Técnicas de Inactivación de Genes/métodos , Genes Reporteros , Animales , Encéfalo/citología , Calcio/metabolismo , Línea Celular , Hibridación Fluorescente in Situ , Luz , Ratones , Ratones Transgénicos , Microscopía Fluorescente , Neuronas/metabolismo , Optogenética , ARN no Traducido/genética , Transgenes/genéticaRESUMEN
Visceral adipose tissue (VAT) hosts a population of regulatory T (Treg) cells, with a unique phenotype, that controls local and systemic inflammation and metabolism. Generation of a T cell receptor transgenic mouse line, wherein VAT Tregs are highly enriched, facilitated study of their provenance, dependencies, and activities. We definitively established a role for T cell receptor specificity, uncovered an unexpected function for the primordial Treg transcription-factor, Foxp3, evidenced a cell-intrinsic role for interleukin-33 receptor, and ordered these dependencies within a coherent scenario. Genesis of the VAT-Treg phenotype entailed a priming step in the spleen, permitting them to exit the lymphoid organs and surveil nonlymphoid tissues, and a final diversification process within VAT, in response to microenvironmental cues. Understanding the principles of tissue-Treg biology is a prerequisite for precision-targeting strategies.
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Grasa Intraabdominal/metabolismo , Receptores de Antígenos de Linfocitos T/genética , Linfocitos T Reguladores/metabolismo , Animales , Ensamble y Desensamble de Cromatina , Factores de Transcripción Forkhead/metabolismo , Proteína 1 Similar al Receptor de Interleucina-1/genética , Proteína 1 Similar al Receptor de Interleucina-1/metabolismo , Grasa Intraabdominal/inmunología , Macrófagos/citología , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , PPAR gamma/genética , PPAR gamma/metabolismo , Fenotipo , ARN/química , ARN/aislamiento & purificación , ARN/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores de Interleucina/metabolismo , Análisis de la Célula Individual , Bazo/inmunología , Bazo/metabolismo , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/inmunología , TranscriptomaRESUMEN
Numerous well-defined classes of retinal ganglion cells innervate the thalamus to guide image-forming vision, yet the rules governing their convergence and divergence remain unknown. Using two-photon calcium imaging in awake mouse thalamus, we observed a functional arrangement of retinal ganglion cell axonal boutons in which coarse-scale retinotopic ordering gives way to fine-scale organization based on shared preferences for other visual features. Specifically, at the â¼6 µm scale, clusters of boutons from different axons often showed similar preferences for either one or multiple features, including axis and direction of motion, spatial frequency, and changes in luminance. Conversely, individual axons could "de-multiplex" information channels by participating in multiple, functionally distinct bouton clusters. Finally, ultrastructural analyses demonstrated that retinal axonal boutons in a local cluster often target the same dendritic domain. These data suggest that functionally specific convergence and divergence of retinal axons may impart diverse, robust, and often novel feature selectivity to visual thalamus.