RESUMEN
The role of the autoimmune regulator (Aire) in central immune tolerance and thymic self-representation was first described more than 20 years ago, but fascinating new insights into its biology continue to emerge, particularly in the era of advanced single-cell genomics. We briefly describe the role of human genetics in the discovery of Aire, as well as insights into its function gained from genotype-phenotype correlations and the spectrum of Aire-associated autoimmunity-including insights from patients with Aire mutations with broad and diverse implications for human health. We then highlight emerging trends in Aire biology, focusing on three topic areas. First, we discuss medullary thymic epithelial diversity and the role of Aire in thymic epithelial development. Second, we highlight recent developments regarding the molecular mechanisms of Aire and its binding partners. Finally, we describe the rapidly evolving biology of the identity and function of extrathymic Aire-expressing cells (eTACs), and a novel eTAC subset called Janus cells, as well as their potential roles in immune homeostasis.
Asunto(s)
Proteína AIRE , Autoinmunidad , Factores de Transcripción , Humanos , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Animales , Timo/inmunología , Timo/metabolismo , Mutación , Tolerancia Inmunológica , Células Epiteliales/metabolismo , Células Epiteliales/inmunología , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/metabolismoRESUMEN
Intrathymic T cell development is a complex process that depends upon continuous guidance from thymus stromal cell microenvironments. The thymic epithelium within the thymic stroma comprises highly specialized cells with a high degree of anatomic, phenotypic, and functional heterogeneity. These properties are collectively required to bias thymocyte development toward production of self-tolerant and functionally competent T cells. The importance of thymic epithelial cells (TECs) is evidenced by clear links between their dysfunction and multiple diseases where autoimmunity and immunodeficiency are major components. Consequently, TECs are an attractive target for cell therapies to restore effective immune system function. The pathways and molecular regulators that control TEC development are becoming clearer, as are their influences on particular stages of T cell development. Here, we review both historical and the most recent advances in our understanding of the cellular and molecular mechanisms controlling TEC development, function, dysfunction, and regeneration.
Asunto(s)
Células Epiteliales/metabolismo , Linfocitos T/fisiología , Timo/patología , Animales , Autoinmunidad , Diferenciación Celular , Células Epiteliales/inmunología , Factores de Transcripción Forkhead/metabolismo , Humanos , Tolerancia Inmunológica , Timo/inmunología , Factores de Transcripción/metabolismo , Proteína AIRERESUMEN
Mucosal barrier immunity is essential for the maintenance of the commensal microflora and combating invasive bacterial infection. Although immune and epithelial cells are thought to be the canonical orchestrators of this complex equilibrium, here, we show that the enteric nervous system (ENS) plays an essential and non-redundant role in governing the antimicrobial protein (AMP) response. Using confocal microscopy and single-molecule fluorescence in situ mRNA hybridization (smFISH) studies, we observed that intestinal neurons produce the pleiotropic cytokine IL-18. Strikingly, deletion of IL-18 from the enteric neurons alone, but not immune or epithelial cells, rendered mice susceptible to invasive Salmonella typhimurium (S.t.) infection. Mechanistically, unbiased RNA sequencing and single-cell sequencing revealed that enteric neuronal IL-18 is specifically required for homeostatic goblet cell AMP production. Together, we show that neuron-derived IL-18 signaling controls tissue-wide intestinal immunity and has profound consequences on the mucosal barrier and invasive bacterial killing.
Asunto(s)
Inmunidad Mucosa/inmunología , Interleucina-18/inmunología , Mucosa Intestinal/inmunología , Animales , Citocinas/inmunología , Sistema Nervioso Entérico/inmunología , Sistema Nervioso Entérico/metabolismo , Células Epiteliales/inmunología , Femenino , Células Caliciformes/inmunología , Interleucina-18/biosíntesis , Mucosa Intestinal/metabolismo , Intestino Delgado/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas/inmunología , Ratas , Ratas Sprague-Dawley , Infecciones por Salmonella/inmunología , Salmonella typhimurium/inmunología , Transducción de Señal/inmunologíaRESUMEN
Throughout a 24-h period, the small intestine (SI) is exposed to diurnally varying food- and microbiome-derived antigenic burdens but maintains a strict immune homeostasis, which when perturbed in genetically susceptible individuals, may lead to Crohn disease. Herein, we demonstrate that dietary content and rhythmicity regulate the diurnally shifting SI epithelial cell (SIEC) transcriptional landscape through modulation of the SI microbiome. We exemplify this concept with SIEC major histocompatibility complex (MHC) class II, which is diurnally modulated by distinct mucosal-adherent SI commensals, while supporting downstream diurnal activity of intra-epithelial IL-10+ lymphocytes regulating the SI barrier function. Disruption of this diurnally regulated diet-microbiome-MHC class II-IL-10-epithelial barrier axis by circadian clock disarrangement, alterations in feeding time or content, or epithelial-specific MHC class II depletion leads to an extensive microbial product influx, driving Crohn-like enteritis. Collectively, we highlight nutritional features that modulate SI microbiome, immunity, and barrier function and identify dietary, epithelial, and immune checkpoints along this axis to be potentially exploitable in future Crohn disease interventions.
Asunto(s)
Enfermedad de Crohn/microbiología , Células Epiteliales/metabolismo , Microbioma Gastrointestinal , Antígenos de Histocompatibilidad Clase II/metabolismo , Intestino Delgado/inmunología , Intestino Delgado/microbiología , Transcriptoma/genética , Animales , Antibacterianos/farmacología , Relojes Circadianos/fisiología , Enfermedad de Crohn/inmunología , Enfermedad de Crohn/metabolismo , Dieta , Células Epiteliales/citología , Células Epiteliales/inmunología , Citometría de Flujo , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/genética , Perfilación de la Expresión Génica , Antígenos de Histocompatibilidad Clase II/genética , Homeostasis , Hibridación Fluorescente in Situ , Interleucina-10/metabolismo , Interleucina-10/farmacología , Intestino Delgado/fisiología , Linfocitos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Periodicidad , Linfocitos T/inmunología , Transcriptoma/fisiologíaRESUMEN
Tumor necrosis factor (TNF) drives chronic inflammation and cell death in the intestine, and blocking TNF is a therapeutic approach in inflammatory bowel disease (IBD). Despite this knowledge, the pathways that protect the intestine from TNF are incompletely understood. Here we demonstrate that group 3 innate lymphoid cells (ILC3s) protect the intestinal epithelium from TNF-induced cell death. This occurs independent of interleukin-22 (IL-22), and we identify that ILC3s are a dominant source of heparin-binding epidermal growth factor-like growth factor (HB-EGF). ILC3s produce HB-EGF in response to prostaglandin E2 (PGE2) and engagement of the EP2 receptor. Mice lacking ILC3-derived HB-EGF exhibit increased susceptibility to TNF-mediated epithelial cell death and experimental intestinal inflammation. Finally, human ILC3s produce HB-EGF and are reduced from the inflamed intestine. These results define an essential role for ILC3-derived HB-EGF in protecting the intestine from TNF and indicate that disruption of this pathway contributes to IBD.
Asunto(s)
Factor de Crecimiento Similar a EGF de Unión a Heparina/inmunología , Inmunidad Innata/inmunología , Inflamación/inmunología , Intestinos/inmunología , Linfocitos/inmunología , Factor de Necrosis Tumoral alfa/inmunología , Animales , Células Epiteliales/inmunología , Mucosa Intestinal/inmunología , Ratones , Ratones Endogámicos C57BL , Transducción de Señal/inmunologíaRESUMEN
Environmental allergens, including fungi, insects and mites, trigger type 2 immunity; however, the innate sensing mechanisms and initial signaling events remain unclear. Herein, we demonstrate that allergens trigger RIPK1-caspase 8 ripoptosome activation in epithelial cells. The active caspase 8 subsequently engages caspases 3 and 7, which directly mediate intracellular maturation and release of IL-33, a pro-atopy, innate immunity, alarmin cytokine. Mature IL-33 maintained functional interaction with the cognate ST2 receptor and elicited potent pro-atopy inflammatory activity in vitro and in vivo. Inhibiting caspase 8 pharmacologically and deleting murine Il33 and Casp8 each attenuated allergic inflammation in vivo. Clinical data substantiated ripoptosome activation and IL-33 maturation as likely contributors to human allergic inflammation. Our findings reveal an epithelial barrier, allergen-sensing mechanism that converges on the ripoptosome as an intracellular molecular signaling platform, triggering type 2 innate immune responses. These findings have significant implications for understanding and treating human allergic diseases.
Asunto(s)
Alérgenos/inmunología , Inmunidad Innata/inmunología , Inflamación/inmunología , Adolescente , Animales , Caspasa 8/inmunología , Línea Celular , Línea Celular Tumoral , Niño , Preescolar , Citocinas/inmunología , Células Epiteliales/inmunología , Femenino , Células HEK293 , Humanos , Hipersensibilidad/inmunología , Interleucina-33/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Transducción de Señal/inmunologíaRESUMEN
Intestinal epithelial cell (IEC) damage by T cells contributes to graft-versus-host disease, inflammatory bowel disease and immune checkpoint blockade-mediated colitis. But little is known about the target cell-intrinsic features that affect disease severity. Here we identified disruption of oxidative phosphorylation and an increase in succinate levels in the IECs from several distinct in vivo models of T cell-mediated colitis. Metabolic flux studies, complemented by imaging and protein analyses, identified disruption of IEC-intrinsic succinate dehydrogenase A (SDHA), a component of mitochondrial complex II, in causing these metabolic alterations. The relevance of IEC-intrinsic SDHA in mediating disease severity was confirmed by complementary chemical and genetic experimental approaches and validated in human clinical samples. These data identify a critical role for the alteration of the IEC-specific mitochondrial complex II component SDHA in the regulation of the severity of T cell-mediated intestinal diseases.
Asunto(s)
Colitis/enzimología , Colon/enzimología , Citotoxicidad Inmunológica , Complejo II de Transporte de Electrones/metabolismo , Células Epiteliales/enzimología , Enfermedad Injerto contra Huésped/enzimología , Mucosa Intestinal/enzimología , Mitocondrias/enzimología , Linfocitos T/inmunología , Animales , Estudios de Casos y Controles , Comunicación Celular , Células Cultivadas , Colitis/genética , Colitis/inmunología , Colitis/patología , Colon/inmunología , Colon/ultraestructura , Modelos Animales de Enfermedad , Complejo II de Transporte de Electrones/genética , Células Epiteliales/inmunología , Células Epiteliales/ultraestructura , Femenino , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/patología , Humanos , Inmunidad Mucosa , Mucosa Intestinal/inmunología , Mucosa Intestinal/ultraestructura , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Mitocondrias/inmunología , Mitocondrias/ultraestructura , Fosforilación Oxidativa , Ácido Succínico/metabolismo , Linfocitos T/metabolismoRESUMEN
Epithelial cells have an ability termed 'cell competition', which is an immune surveillance-like function that extrudes precancerous cells from the epithelial layer, leading to apoptosis and clearance. However, it remains unclear how epithelial cells recognize and extrude transformed cells. Here, we discovered that a PirB family protein, leukocyte immunoglobulin-like receptor B3 (LILRB3), which is expressed on non-transformed epithelial cells, recognizes major histocompatibility complex class I (MHC class I) that is highly expressed on transformed cells. MHC class I interaction with LILRB3 expressed on normal epithelial cells triggers an SHP2-ROCK2 pathway that generates a mechanical force to extrude transformed cells. Removal of transformed cells occurs independently of natural killer (NK) cell or CD8+ cytotoxic T cell-mediated activity. This is a new mechanism in that the immunological ligand-receptor system generates a mechanical force in non-immune epithelial cells to extrude precancerous cells in the same epithelial layer.
Asunto(s)
Antígenos CD/metabolismo , Apoptosis , Competencia Celular , Células Epiteliales/metabolismo , Antígenos de Histocompatibilidad Clase I/metabolismo , Neoplasias Pulmonares/metabolismo , Lesiones Precancerosas/metabolismo , Receptores Inmunológicos/metabolismo , Animales , Antígenos CD/genética , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Perros , Células Epiteliales/inmunología , Células Epiteliales/patología , Células HaCaT , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Células de Riñón Canino Madin Darby , Mecanotransducción Celular , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Lesiones Precancerosas/genética , Lesiones Precancerosas/inmunología , Lesiones Precancerosas/patología , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Células RAW 264.7 , Receptores Inmunológicos/genética , Estrés Mecánico , Quinasas Asociadas a rho/metabolismoRESUMEN
The intestinal epithelium interacts with immune cells to support tissue homeostasis and coordinate responses against pathogens. In this issue of Immunity, Yang et al. unveil a central role for mast cell-epithelial cell interactions in orchestrating protective type 2 immune responses following intestinal helminth infection.
Asunto(s)
Mucosa Intestinal , Mastocitos , Mastocitos/inmunología , Animales , Mucosa Intestinal/inmunología , Mucosa Intestinal/parasitología , Humanos , Homeostasis/inmunología , Helmintiasis/inmunología , Helmintiasis/parasitología , Células Epiteliales/inmunología , RatonesRESUMEN
Skin inflammation is potentiated by coordinated epithelial and immune cell metabolism. In this issue of Immunity, Subudhi and Konieczny et al. delineate how HIF1α regulates epithelial cell glycolysis during psoriasis. In turn, lactate is a byproduct that augments type 17 γδ T cell responses to sustain inflammatory skin disease.
Asunto(s)
Células Epiteliales , Glucólisis , Subunidad alfa del Factor 1 Inducible por Hipoxia , Psoriasis , Piel , Animales , Humanos , Enfermedad Crónica , Células Epiteliales/metabolismo , Células Epiteliales/inmunología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Inflamación/inmunología , Inflamación/metabolismo , Psoriasis/inmunología , Psoriasis/metabolismo , Piel/inmunología , Piel/patología , Piel/metabolismoRESUMEN
Upon parasitic helminth infection, activated intestinal tuft cells secrete interleukin-25 (IL-25), which initiates a type 2 immune response during which lamina propria type 2 innate lymphoid cells (ILC2s) produce IL-13. This causes epithelial remodeling, including tuft cell hyperplasia, the function of which is unknown. We identified a cholinergic effector function of tuft cells, which are the only epithelial cells that expressed choline acetyltransferase (ChAT). During parasite infection, mice with epithelial-specific deletion of ChAT had increased worm burden, fitness, and fecal egg counts, even though type 2 immune responses were comparable. Mechanistically, IL-13-amplified tuft cells release acetylcholine (ACh) into the gut lumen. Finally, we demonstrated a direct effect of ACh on worms, which reduced their fecundity via helminth-expressed muscarinic ACh receptors. Thus, tuft cells are sentinels in naive mice, and their amplification upon helminth infection provides an additional type 2 immune response effector function.
Asunto(s)
Acetilcolina , Mucosa Intestinal , Animales , Acetilcolina/metabolismo , Ratones , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/parasitología , Colina O-Acetiltransferasa/metabolismo , Interleucina-13/metabolismo , Interleucina-13/inmunología , Ratones Noqueados , Ratones Endogámicos C57BL , Helmintiasis/inmunología , Helmintiasis/parasitología , Células Epiteliales/inmunología , Células Epiteliales/metabolismo , Inmunidad Innata , Nematospiroides dubius/inmunología , Células en PenachoRESUMEN
Epithelial cells secrete chloride to regulate water release at mucosal barriers, supporting both homeostatic hydration and the "weep" response that is critical for type 2 immune defense against parasitic worms (helminths). Epithelial tuft cells in the small intestine sense helminths and release cytokines and lipids to activate type 2 immune cells, but whether they regulate epithelial secretion is unknown. Here, we found that tuft cell activation rapidly induced epithelial chloride secretion in the small intestine. This response required tuft cell sensory functions and tuft cell-derived acetylcholine (ACh), which acted directly on neighboring epithelial cells to stimulate chloride secretion, independent of neurons. Maximal tuft cell-induced chloride secretion coincided with immune restriction of helminths, and clearance was delayed in mice lacking tuft cell-derived ACh, despite normal type 2 inflammation. Thus, we have uncovered an epithelium-intrinsic response unit that uses ACh to couple tuft cell sensing to the secretory defenses of neighboring epithelial cells.
Asunto(s)
Acetilcolina , Cloruros , Células Epiteliales , Mucosa Intestinal , Animales , Acetilcolina/metabolismo , Ratones , Cloruros/metabolismo , Células Epiteliales/metabolismo , Células Epiteliales/parasitología , Células Epiteliales/inmunología , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/parasitología , Intestino Delgado/inmunología , Intestino Delgado/parasitología , Intestino Delgado/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Células en PenachoRESUMEN
A specialized population of mast cells residing within epithelial layers, currently known as intraepithelial mast cells (IEMCs), was originally observed over a century ago, yet their physiological functions have remained enigmatic. In this study, we unveil an unexpected and crucial role of IEMCs in driving gasdermin C-mediated type 2 immunity. During helminth infection, αEß7 integrin-positive IEMCs engaged in extensive intercellular crosstalk with neighboring intestinal epithelial cells (IECs). Through the action of IEMC-derived proteases, gasdermin C proteins intrinsic to the epithelial cells underwent cleavage, leading to the release of a critical type 2 cytokine, interleukin-33 (IL-33). Notably, mast cell deficiency abolished the gasdermin C-mediated immune cascade initiated by epithelium. These findings shed light on the functions of IEMCs, uncover a previously unrecognized phase of type 2 immunity involving mast cell-epithelial cell crosstalk, and advance our understanding of the cellular mechanisms underlying gasdermin C activation.
Asunto(s)
Interleucina-33 , Mastocitos , Proteínas de Unión a Fosfato , Proteínas Citotóxicas Formadoras de Poros , Animales , Ratones , Comunicación Celular/inmunología , Células Epiteliales/inmunología , Células Epiteliales/metabolismo , Interleucina-33/metabolismo , Interleucina-33/inmunología , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/inmunología , Mastocitos/inmunología , Mastocitos/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de Unión a Fosfato/metabolismo , Proteínas Citotóxicas Formadoras de Poros/inmunología , Proteínas Citotóxicas Formadoras de Poros/metabolismoRESUMEN
The nasal mucosa is often the initial site of respiratory viral infection, replication, and transmission. Understanding how infection shapes tissue-scale primary and memory responses is critical for designing mucosal therapeutics and vaccines. We generated a single-cell RNA-sequencing atlas of the murine nasal mucosa, sampling three regions during primary influenza infection and rechallenge. Compositional analysis revealed restricted infection to the respiratory mucosa with stepwise changes in immune and epithelial cell subsets and states. We identified and characterized a rare subset of Krt13+ nasal immune-interacting floor epithelial (KNIIFE) cells, which concurrently increased with tissue-resident memory T (TRM)-like cells. Proportionality analysis, cell-cell communication inference, and microscopy underscored the CXCL16-CXCR6 axis between KNIIFE and TRM cells. Secondary influenza challenge induced accelerated and coordinated myeloid and lymphoid responses without epithelial proliferation. Together, this atlas serves as a reference for viral infection in the upper respiratory tract and highlights the efficacy of local coordinated memory responses.
Asunto(s)
Memoria Inmunológica , Células T de Memoria , Mucosa Nasal , Infecciones por Orthomyxoviridae , Animales , Memoria Inmunológica/inmunología , Ratones , Mucosa Nasal/virología , Mucosa Nasal/inmunología , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/virología , Células T de Memoria/inmunología , Células Epiteliales/inmunología , Células Epiteliales/virología , Ratones Endogámicos C57BL , Humanos , Análisis de la Célula Individual , Gripe Humana/inmunología , Gripe Humana/virología , Femenino , Receptores CXCR6/metabolismo , Receptores CXCR6/inmunología , Virus de la Influenza A/inmunología , Virus de la Influenza A/fisiologíaRESUMEN
The immune system safeguards organ integrity by employing a balancing act of inflammatory and immunosuppressive mechanisms designed to neutralize foreign invaders and resolve injury. Maintaining or restoring a state of immune homeostasis is particularly challenging at barrier sites where constant exposure to immunogenic environmental agents may induce destructive inflammation. Recent studies underscore the role of epithelial and mesenchymal barrier cells in regulating immune cell function and local homeostatic and inflammatory responses. Here, we highlight immunoregulatory circuits engaging epithelial and mesenchymal cells in the intestine, airways, and skin and discuss how immune communications with hematopoietic cells and the microbiota orchestrate local immune homeostasis and inflammation.
Asunto(s)
Epitelio/inmunología , Homeostasis , Inflamación/inmunología , Mesodermo/inmunología , Animales , Células Epiteliales/inmunología , Humanos , Infecciones/inmunología , Intestinos/citología , Intestinos/inmunología , Intestinos/fisiología , Mesodermo/citología , Sistema Respiratorio/inmunologíaRESUMEN
The interleukin (IL)-17 family, consisting of six members, promotes host defense but can in some context promote the development of autoimmune disease. Here, we examined the role of IL-17D, a poorly understood member in the IL-17 family. IL-17D was expressed primarily by colonic epithelial cells. Il17d-/- mice were more susceptible to acute colitis, bacterial infection and experimentally induced colon cancer than their wildtype counterparts. Il17d deficiency impaired IL-22 production by group 3 innate lymphoid cells (ILC3s) and reduced expression of IL-22-dependent antimicrobial peptides, RegIIIß and RegIIIγ, in colon tissue at steady state and in colitis; this was associated with changes in microbial composition and dysbiosis. Protein purification studies revealed that IL-17D bound not canonical IL-17 receptors, but rather CD93, a glycoprotein expressed on mature ILC3s. Mice lacking Cd93 in ILC3s exhibited impaired IL-22 production and aggravated colonic inflammation in experimental colitis. Thus, an IL-17D-CD93 axis regulates ILC3 function to preserve intestinal homeostasis.
Asunto(s)
Inmunidad Innata/inmunología , Interleucina-27/inmunología , Linfocitos/inmunología , Glicoproteínas de Membrana/inmunología , Animales , Línea Celular , Colitis/inmunología , Colon/inmunología , Células Epiteliales/inmunología , Interleucinas/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Células RAW 264.7 , Interleucina-22RESUMEN
Two sets of innate immune proteins detect pathogens. Pattern recognition receptors (PRRs) bind microbial products, whereas guard proteins detect virulence factor activities by the surveillance of homeostatic processes within cells. While PRRs are well known for their roles in many types of infections, the role of guard proteins in most infectious contexts remains less understood. Here, we demonstrated that inhibition of protein synthesis during viral infection is sensed as a virulence strategy and initiates pyroptosis in human keratinocytes. We identified the BCL-2 family members MCL-1 and BCL-xL as sensors of translation shutdown. Virus- or chemical-induced translation inhibition resulted in MCL-1 depletion and inactivation of BCL-xL, leading to mitochondrial damage, caspase-3-dependent cleavage of gasdermin E, and release of interleukin-1α (IL-1α). Blocking this pathway enhanced virus replication in an organoid model of human skin. Thus, MCL-1 and BCL-xL can act as guard proteins within barrier epithelia and contribute to antiviral defense.
Asunto(s)
Apoptosis/inmunología , Células Epiteliales/inmunología , Proteínas Proto-Oncogénicas c-bcl-2/inmunología , Piroptosis/inmunología , Receptores de Estrógenos/inmunología , Virus/inmunología , Animales , Proteínas Reguladoras de la Apoptosis/inmunología , Caspasa 3/inmunología , Línea Celular , Chlorocebus aethiops , Células HEK293 , Humanos , Interleucina-1alfa/inmunología , Ratones , Mitocondrias/inmunología , Células 3T3 NIH , Células Vero , Replicación Viral/inmunología , Proteína bcl-X/inmunologíaRESUMEN
Intestinal Th17 cells are induced and accumulate in response to colonization with a subgroup of intestinal microbes such as segmented filamentous bacteria (SFB) and certain extracellular pathogens. Here, we show that adhesion of microbes to intestinal epithelial cells (ECs) is a critical cue for Th17 induction. Upon monocolonization of germ-free mice or rats with SFB indigenous to mice (M-SFB) or rats (R-SFB), M-SFB and R-SFB showed host-specific adhesion to small intestinal ECs, accompanied by host-specific induction of Th17 cells. Citrobacter rodentium and Escherichia coli O157 triggered similar Th17 responses, whereas adhesion-defective mutants of these microbes failed to do so. Moreover, a mixture of 20 bacterial strains, which were selected and isolated from fecal samples of a patient with ulcerative colitis on the basis of their ability to cause a robust induction of Th17 cells in the mouse colon, also exhibited EC-adhesive characteristics.
Asunto(s)
Adhesión Bacteriana , Citrobacter rodentium/fisiología , Infecciones por Enterobacteriaceae/inmunología , Infecciones por Escherichia coli/inmunología , Escherichia coli O157/fisiología , Mucosa Intestinal/inmunología , Células Th17/inmunología , Animales , Infecciones Bacterianas/inmunología , Células Epiteliales/inmunología , Células Epiteliales/microbiología , Células Epiteliales/ultraestructura , Heces/microbiología , Humanos , Inmunoglobulina A/inmunología , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos , Microscopía Electrónica de Rastreo , Ratas , Ratas Endogámicas F344 , Especificidad de la EspecieRESUMEN
An ideal vaccine both attenuates virus growth and disease in infected individuals and reduces the spread of infections in the population, thereby generating herd immunity. Although this strategy has proved successful by generating humoral immunity to measles, yellow fever and polio, many respiratory viruses evolve to evade pre-existing antibodies1. One approach for improving the breadth of antiviral immunity against escape variants is through the generation of memory T cells in the respiratory tract, which are positioned to respond rapidly to respiratory virus infections2-6. However, it is unknown whether memory T cells alone can effectively surveil the respiratory tract to the extent that they eliminate or greatly reduce viral transmission following exposure of an individual to infection. Here we use a mouse model of natural parainfluenza virus transmission to quantify the extent to which memory CD8+ T cells resident in the respiratory tract can provide herd immunity by reducing both the susceptibility of acquiring infection and the extent of transmission, even in the absence of virus-specific antibodies. We demonstrate that protection by resident memory CD8+ T cells requires the antiviral cytokine interferon-γ (IFNγ) and leads to altered transcriptional programming of epithelial cells within the respiratory tract. These results suggest that tissue-resident CD8+ T cells in the respiratory tract can have important roles in protecting the host against viral disease and limiting viral spread throughout the population.
Asunto(s)
Linfocitos T CD8-positivos , Memoria Inmunológica , Células T de Memoria , Infecciones por Paramyxoviridae , Sistema Respiratorio , Animales , Ratones , Linfocitos T CD8-positivos/inmunología , Modelos Animales de Enfermedad , Células Epiteliales/inmunología , Células Epiteliales/metabolismo , Inmunidad Colectiva/inmunología , Memoria Inmunológica/inmunología , Interferón gamma/inmunología , Células T de Memoria/inmunología , Paramyxoviridae/inmunología , Paramyxoviridae/fisiología , Infecciones por Paramyxoviridae/inmunología , Infecciones por Paramyxoviridae/prevención & control , Infecciones por Paramyxoviridae/transmisión , Infecciones por Paramyxoviridae/virología , Sistema Respiratorio/citología , Sistema Respiratorio/inmunología , Sistema Respiratorio/virología , Transcripción Genética , HumanosRESUMEN
The COVID-19 pandemic is an ongoing global health threat, yet our understanding of the dynamics of early cellular responses to this disease remains limited1. Here in our SARS-CoV-2 human challenge study, we used single-cell multi-omics profiling of nasopharyngeal swabs and blood to temporally resolve abortive, transient and sustained infections in seronegative individuals challenged with pre-Alpha SARS-CoV-2. Our analyses revealed rapid changes in cell-type proportions and dozens of highly dynamic cellular response states in epithelial and immune cells associated with specific time points and infection status. We observed that the interferon response in blood preceded the nasopharyngeal response. Moreover, nasopharyngeal immune infiltration occurred early in samples from individuals with only transient infection and later in samples from individuals with sustained infection. High expression of HLA-DQA2 before inoculation was associated with preventing sustained infection. Ciliated cells showed multiple immune responses and were most permissive for viral replication, whereas nasopharyngeal T cells and macrophages were infected non-productively. We resolved 54 T cell states, including acutely activated T cells that clonally expanded while carrying convergent SARS-CoV-2 motifs. Our new computational pipeline Cell2TCR identifies activated antigen-responding T cells based on a gene expression signature and clusters these into clonotype groups and motifs. Overall, our detailed time series data can serve as a Rosetta stone for epithelial and immune cell responses and reveals early dynamic responses associated with protection against infection.