RESUMEN
Gastrointestinal nematode (GIN) infection has applied significant evolutionary pressure to the mammalian immune system and remains a global economic and human health burden. Upon infection, type 2 immune sentinels activate a common antihelminth response that mobilizes and remodels the intestinal tissue for effector function; however, there is growing appreciation of the impact GIN infection also has on the distal tissue immune state. Indeed, this effect is observed even in tissues through which GINs never transit. This review highlights how GIN infection modulates systemic immunity through (a) induction of host resistance and tolerance responses, (b) secretion of immunomodulatory products, and (c) interaction with the intestinal microbiome. It also discusses the direct consequences that changes to distal tissue immunity can have for concurrent and subsequent infection, chronic noncommunicable diseases, and vaccination efficacy.
Asunto(s)
Microbioma Gastrointestinal , Nematodos , Infecciones por Nematodos , Animales , Humanos , Infecciones por Nematodos/inmunología , Nematodos/inmunología , Nematodos/fisiología , Microbioma Gastrointestinal/inmunología , Inmunomodulación , Interacciones Huésped-Parásitos/inmunología , Parasitosis Intestinales/inmunología , Tolerancia Inmunológica , Tracto Gastrointestinal/inmunología , Tracto Gastrointestinal/parasitologíaRESUMEN
Type 2 immunity mediates protective responses to helminths and pathological responses to allergens, but it also has broad roles in the maintenance of tissue integrity, including wound repair. Type 2 cytokines are known to promote fibrosis, an overzealous repair response, but their contribution to healthy wound repair is less well understood. This review discusses the evidence that the canonical type 2 cytokines, IL-4 and IL-13, are integral to the tissue repair process through two main pathways. First, essential for the progression of effective tissue repair, IL-4 and IL-13 suppress the initial inflammatory response to injury. Second, these cytokines regulate how the extracellular matrix is modified, broken down, and rebuilt for effective repair. IL-4 and/or IL-13 amplifies multiple aspects of the tissue repair response, but many of these pathways are highly redundant and can be induced by other signals. Therefore, the exact contribution of IL-4Rα signaling remains difficult to unravel.
Asunto(s)
Interleucina-13 , Interleucina-4 , Animales , Humanos , Citocinas/metabolismo , Fibrosis , HelmintosRESUMEN
A principal purpose of type 2 immunity was thought to be defense against large parasites, but it also functions in the restoration of homeostasis, such as toxin clearance following snake bites. In other cases, like allergy, the type 2 T helper (Th2) cytokines and cells present in the environment are detrimental and cause diseases. In recent years, the recognition of cell heterogeneity within Th2-associated cell populations has revealed specific functions of cells with a particular phenotype or gene signature. In addition, here we discuss the recent data regarding heterogeneity of type 2 immunity-related cells, as well as their newly identified role in a variety of processes ranging from involvement in respiratory viral infections [especially in the context of the recent COVID-19 (coronavirus disease 2019) pandemic] to control of cancer development or of metabolic homeostasis.
Asunto(s)
COVID-19 , Hipersensibilidad , Animales , Citocinas/metabolismo , Homeostasis , Humanos , Linfocitos T Colaboradores-Inductores/metabolismo , Células Th2RESUMEN
Our understanding of the functions of the IL-1 superfamily cytokine and damage-associated molecular pattern IL-33 continues to evolve with our understanding of homeostasis and immunity. The early findings that IL-33 is a potent driver of type 2 immune responses promoting parasite expulsion, but also inflammatory diseases like allergy and asthma, have been further supported. Yet, as the importance of a type 2 response in tissue repair and homeostasis has emerged, so has the fundamental importance of IL-33 to these processes. In this review, we outline an evolving understanding of IL-33 immunobiology, paying particular attention to how IL-33 directs a network of ST2+ regulatory T cells, reparative and regulatory macrophages, and type 2 innate lymphoid cells that are fundamental to tissue development, homeostasis, and repair.
Asunto(s)
Hipersensibilidad , Interleucina-33 , Animales , Citocinas , Homeostasis , Humanos , Inmunidad Innata , LinfocitosRESUMEN
Type 2 immunity helps protect the host from infection, but it also plays key roles in tissue homeostasis, metabolism, and repair. Unfortunately, inappropriate type 2 immune reactions may lead to allergy and asthma. Group 2 innate lymphoid cells (ILC2s) in the lungs respond rapidly to local environmental cues, such as the release of epithelium-derived type 2 initiator cytokines/alarmins, producing type 2 effector cytokines such as IL-4, IL-5, and IL-13 in response to tissue damage and infection. ILC2s are associated with the severity of allergic asthma, and experimental models of lung inflammation have shown how they act as playmakers, receiving signals variously from stromal and immune cells as well as the nervous system and then distributing cytokine cues to elicit type 2 immune effector functions and potentiate CD4+ T helper cell activation, both of which characterize the pathology of allergic asthma. Recent breakthroughs identifying stromal- and neuronal-derived microenvironmental cues that regulate ILC2s, along with studies recognizing the potential plasticity of ILC2s, have improved our understanding of the immunoregulation of asthma and opened new avenues for drug discovery.
Asunto(s)
Asma , Hipersensibilidad , Animales , Asma/etiología , Humanos , Inmunidad Innata , Interleucina-13 , LinfocitosRESUMEN
Tuft cells-rare solitary chemosensory cells in mucosal epithelia-are undergoing intense scientific scrutiny fueled by recent discovery of unsuspected connections to type 2 immunity. These cells constitute a conduit by which ligands from the external space are sensed via taste-like signaling pathways to generate outputs unique among epithelial cells: the cytokine IL-25, eicosanoids associated with allergic immunity, and the neurotransmitter acetylcholine. The classic type II taste cell transcription factor POU2F3 is lineage defining, suggesting a conceptualization of these cells as widely distributed environmental sensors with effector functions interfacing type 2 immunity and neural circuits. Increasingly refined single-cell analytics have revealed diversity among tuft cells that extends from nasal epithelia and type II taste cells to ex-Aire-expressing medullary thymic cells and small-intestine cells that mediate tissue remodeling in response to colonizing helminths and protists.
Asunto(s)
Epitelio/fisiología , Helmintiasis/inmunología , Helmintos/fisiología , Factores de Transcripción de Octámeros/metabolismo , Células Receptoras Sensoriales/fisiología , Células Th2/inmunología , Animales , Humanos , Sistema Inmunológico , Interleucina-17/metabolismo , Sistema Nervioso , Neuroinmunomodulación , Factores de Transcripción de Octámeros/genética , Transducción de Señal , Canales Catiónicos TRPM/metabolismoRESUMEN
Although enteric helminth infections modulate immunity to mucosal pathogens, their effects on systemic microbes remain less established. Here, we observe increased mortality in mice coinfected with the enteric helminth Heligmosomoides polygyrus bakeri (Hpb) and West Nile virus (WNV). This enhanced susceptibility is associated with altered gut morphology and transit, translocation of commensal bacteria, impaired WNV-specific T cell responses, and increased virus infection in the gastrointestinal tract and central nervous system. These outcomes were due to type 2 immune skewing, because coinfection in Stat6-/- mice rescues mortality, treatment of helminth-free WNV-infected mice with interleukin (IL)-4 mirrors coinfection, and IL-4 receptor signaling in intestinal epithelial cells mediates the susceptibility phenotypes. Moreover, tuft cell-deficient mice show improved outcomes with coinfection, whereas treatment of helminth-free mice with tuft cell-derived cytokine IL-25 or ligand succinate worsens WNV disease. Thus, helminth activation of tuft cell-IL-4-receptor circuits in the gut exacerbates infection and disease of a neurotropic flavivirus.
Asunto(s)
Coinfección , Nematospiroides dubius/fisiología , Transducción de Señal , Infecciones por Strongylida/patología , Virus del Nilo Occidental/fisiología , Animales , Linfocitos T CD8-positivos/inmunología , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Mucosa Intestinal/parasitología , Mucosa Intestinal/virología , Ratones , Ratones Endogámicos C57BL , Neuronas/parasitología , Neuronas/virología , Receptores de Interleucina-4/metabolismo , Factor de Transcripción STAT6/genética , Índice de Severidad de la Enfermedad , Infecciones por Strongylida/parasitologíaRESUMEN
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
Tuft cells in mucosal tissues are key regulators of type 2 immunity. Here, we examined the impact of the microbiota on tuft cell biology in the intestine. Succinate induction of tuft cells and type 2 innate lymphoid cells was elevated with loss of gut microbiota. Colonization with butyrate-producing bacteria or treatment with butyrate suppressed this effect and reduced intestinal histone deacetylase activity. Epithelial-intrinsic deletion of the epigenetic-modifying enzyme histone deacetylase 3 (HDAC3) inhibited tuft cell expansion in vivo and impaired type 2 immune responses during helminth infection. Butyrate restricted stem cell differentiation into tuft cells, and inhibition of HDAC3 in adult mice and human intestinal organoids blocked tuft cell expansion. Collectively, these data define a HDAC3 mechanism in stem cells for tuft cell differentiation that is dampened by a commensal metabolite, revealing a pathway whereby the microbiota calibrate intestinal type 2 immunity.
Asunto(s)
Mucosa Intestinal , Microbiota , Adulto , Ratones , Humanos , Animales , Células en Penacho , Butiratos/farmacología , Butiratos/metabolismo , Inmunidad Innata , Linfocitos/metabolismo , Intestinos , Histona Desacetilasas/metabolismo , Diferenciación CelularRESUMEN
Different effector arms of the immune system are optimized to protect from different classes of pathogens. In some cases, pathogens manipulate the host immune system to promote the wrong type of effector response-a phenomenon known as immune deviation. Typically, immune deviation helps pathogens to avoid destructive immune responses. Here, we report on a type of immune deviation whereby an opportunistic pathogen, Pseudomonas aeruginosa (P. aeruginosa), induces the type 2 immune response resulting in mucin production that is used as an energy source by the pathogen. Specifically, P. aeruginosa-secreted toxin, LasB, processed and activated epithelial amphiregulin to induce type 2 inflammation and mucin production. This "niche remodeling" by P. aeruginosa promoted colonization and, as a by-product, allergic sensitization. Our study thus reveals a type of bacterial immune deviation by increasing nutrient supply. It also uncovers a mechanism of allergic sensitization by a bacterial virulence factor.
Asunto(s)
Infecciones por Pseudomonas , Pseudomonas aeruginosa , Proteínas Bacterianas , Humanos , Inflamación , MucinasRESUMEN
Allergic immunity is orchestrated by group 2 innate lymphoid cells (ILC2s) and type 2 helper T (Th2) cells prominently arrayed at epithelial- and microbial-rich barriers. However, ILC2s and Th2 cells are also present in fibroblast-rich niches within the adventitial layer of larger vessels and similar boundary structures in sterile deep tissues, and it remains unclear whether they undergo dynamic repositioning during immune perturbations. Here, we used thick-section quantitative imaging to show that allergic inflammation drives invasion of lung and liver non-adventitial parenchyma by ILC2s and Th2 cells. However, during concurrent type 1 and type 2 mixed inflammation, IFNγ from broadly distributed type 1 lymphocytes directly blocked both ILC2 parenchymal trafficking and subsequent cell survival. ILC2 and Th2 cell confinement to adventitia limited mortality by the type 1 pathogen Listeria monocytogenes. Our results suggest that the topography of tissue lymphocyte subsets is tightly regulated to promote appropriately timed and balanced immunity.
Asunto(s)
Inflamación/inmunología , Interferón gamma/inmunología , Subgrupos Linfocitarios/inmunología , Células Th2/inmunología , Animales , Muerte Celular/inmunología , Movimiento Celular/inmunología , Hipersensibilidad/inmunología , Inmunidad Innata , Interleucina-33/inmunología , Interleucina-5/metabolismo , Listeria monocytogenes , Listeriosis/inmunología , Listeriosis/mortalidad , Hígado/inmunología , Pulmón/inmunología , Subgrupos Linfocitarios/metabolismo , Lisofosfolípidos/inmunología , Ratones , Tejido Parenquimatoso/inmunología , Esfingosina/análogos & derivados , Esfingosina/inmunología , Células TH1/inmunología , Células Th2/metabolismoRESUMEN
Demodex mites are commensal parasites of hair follicles (HFs). Normally asymptomatic, inflammatory outgrowth of mites can accompany malnutrition, immune dysfunction, and aging, but mechanisms restricting Demodex outgrowth are not defined. Here, we show that control of mite HF colonization in mice required group 2 innate lymphoid cells (ILC2s), interleukin-13 (IL-13), and its receptor, IL-4Ra-IL-13Ra1. HF-associated ILC2s elaborated IL-13 that attenuated HFs and epithelial proliferation at anagen onset; in their absence, Demodex colonization led to increased epithelial proliferation and replacement of gene programs for repair by aberrant inflammation, leading to the loss of barrier function and HF exhaustion. Humans with rhinophymatous acne rosacea, an inflammatory condition associated with Demodex, had increased HF inflammation with decreased type 2 cytokines, consistent with the inverse relationship seen in mice. Our studies uncover a key role for skin ILC2s and IL-13, which comprise an immune checkpoint that sustains cutaneous integrity and restricts pathologic infestation by colonizing HF mites.
Asunto(s)
Infestaciones por Ácaros , Ácaros , Animales , Citocinas , Folículo Piloso/patología , Humanos , Inmunidad Innata , Inflamación , Interleucina-13 , Linfocitos/patología , Ratones , Infestaciones por Ácaros/complicaciones , Infestaciones por Ácaros/parasitología , Infestaciones por Ácaros/patología , SimbiosisRESUMEN
Paneth cells are the primary source of C-type lysozyme, a ß-1,4-N-acetylmuramoylhydrolase that enzymatically processes bacterial cell walls. Paneth cells are normally present in human cecum and ascending colon, but are rarely found in descending colon and rectum; Paneth cell metaplasia in this region and aberrant lysozyme production are hallmarks of inflammatory bowel disease (IBD) pathology. Here, we examined the impact of aberrant lysozyme production in colonic inflammation. Targeted disruption of Paneth cell lysozyme (Lyz1) protected mice from experimental colitis. Lyz1-deficiency diminished intestinal immune responses to bacterial molecular patterns and resulted in the expansion of lysozyme-sensitive mucolytic bacteria, including Ruminococcus gnavus, a Crohn's disease-associated pathobiont. Ectopic lysozyme production in colonic epithelium suppressed lysozyme-sensitive bacteria and exacerbated colitis. Transfer of R. gnavus into Lyz1-/- hosts elicited a type 2 immune response, causing epithelial reprograming and enhanced anti-colitogenic capacity. In contrast, in lysozyme-intact hosts, processed R. gnavus drove pro-inflammatory responses. Thus, Paneth cell lysozyme balances intestinal anti- and pro-inflammatory responses, with implications for IBD.
Asunto(s)
Clostridiales/inmunología , Colitis Ulcerosa/patología , Muramidasa/genética , Muramidasa/metabolismo , Células de Paneth/metabolismo , Animales , Clostridiales/genética , Colitis Ulcerosa/microbiología , Enfermedad de Crohn/patología , Femenino , Microbioma Gastrointestinal/genética , Células Caliciformes/citología , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Factor de Transcripción STAT6/genéticaRESUMEN
Allergies are considered to represent mal-directed type 2 immune responses against mostly innocuous exogenous compounds. Immunoglobulin E (IgE) antibodies are a characteristic feature of allergies and mediate hypersensitivity against allergens through activation of effector cells, particularly mast cells (MCs). Although the physiological functions of this dangerous branch of immunity have remained enigmatic, recent evidence shows that allergic immune reactions can help to protect against the toxicity of venoms. Because bacteria are a potent alternative source of toxins, we assessed the possible role of allergy-like type 2 immunity in antibacterial host defense. We discovered that the adaptive immune response against Staphylococcus aureus (SA) skin infection substantially improved systemic host defense against secondary SA infections in mice. Moreover, this acquired protection depended on IgE effector mechanisms and MCs. Importantly, our results reveal a previously unknown physiological function of allergic immune responses, IgE antibodies, and MCs in host defense against a pathogenic bacterium.
Asunto(s)
Inmunidad Adaptativa/inmunología , Inmunoglobulina E/inmunología , Mastocitos/inmunología , Infecciones Estafilocócicas/inmunología , Infecciones Cutáneas Estafilocócicas/inmunología , Staphylococcus aureus/inmunología , Alérgenos/inmunología , Animales , Femenino , Hipersensibilidad/inmunología , Hipersensibilidad/microbiología , Mastocitos/microbiología , Ratones , Ratones Endogámicos C57BL , Piel/inmunología , Piel/microbiología , Infecciones Estafilocócicas/microbiología , Infecciones Cutáneas Estafilocócicas/microbiologíaRESUMEN
Group 2 innate lymphoid cells (ILC2s) regulate immunity, inflammation, and tissue homeostasis. Two distinct subsets of ILC2s have been described: steady-state natural ILC2s and inflammatory ILC2s, which are elicited following helminth infection. However, how tissue-specific cues regulate these two subsets of ILC2s and their effector functions remains elusive. Here, we report that interleukin-33 (IL-33) promotes the generation of inflammatory ILC2s (ILC2INFLAM) via induction of the enzyme tryptophan hydroxylase 1 (Tph1). Tph1 expression was upregulated in ILC2s upon activation with IL-33 or following helminth infection in an IL-33-dependent manner. Conditional deletion of Tph1 in lymphocytes resulted in selective impairment of ILC2INFLAM responses and increased susceptibility to helminth infection. Further, RNA sequencing analysis revealed altered gene expression in Tph1 deficient ILC2s including inducible T cell co-stimulator (Icos). Collectively, these data reveal a previously unrecognized function for IL-33, Tph1, and ICOS in promoting inflammatory ILC2 responses and type 2 immunity at mucosal barriers.
Asunto(s)
Inmunidad Celular , Proteína Coestimuladora de Linfocitos T Inducibles/inmunología , Interleucina-33/inmunología , Nippostrongylus/inmunología , Infecciones por Strongylida/inmunología , Subgrupos de Linfocitos T/inmunología , Triptófano Hidroxilasa/inmunología , Animales , Linaje de la Célula/genética , Linaje de la Célula/inmunología , Susceptibilidad a Enfermedades , Regulación de la Expresión Génica/inmunología , Inmunidad Innata , Inmunidad Mucosa , Proteína Coestimuladora de Linfocitos T Inducibles/genética , Interleucina-33/genética , Larva/crecimiento & desarrollo , Larva/inmunología , Larva/patogenicidad , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/parasitología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Nippostrongylus/crecimiento & desarrollo , Nippostrongylus/patogenicidad , Cultivo Primario de Células , Transducción de Señal , Infecciones por Strongylida/genética , Infecciones por Strongylida/parasitología , Infecciones por Strongylida/patología , Subgrupos de Linfocitos T/clasificación , Subgrupos de Linfocitos T/parasitología , Triptófano Hidroxilasa/genéticaRESUMEN
Type 2 lymphocytes promote both physiologic tissue remodeling and allergic pathology, yet their physical tissue niches are poorly described. Here, we used quantitative imaging to define the tissue niches of group 2 innate lymphoid cells (ILC2s), which are critical instigators of type 2 immunity. We identified a dominant adventitial niche around lung bronchi and larger vessels in multiple tissues, where ILC2s localized with subsets of dendritic and regulatory T cells. However, ILC2s were most intimately associated with adventitial stromal cells (ASCs), a mesenchymal fibroblast-like subset that expresses interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP). In vitro, ASCs produced TSLP that supported ILC2 accumulation and activation. ILC2s and IL-13 drove reciprocal ASC expansion and IL-33 expression. During helminth infection, ASC depletion impaired lung ILC2 and Th2 cell accumulation and function, which are in part dependent on ASC-derived IL-33. These data indicate that adventitial niches are conserved sites where ASCs regulate type 2 lymphocyte expansion and function.
Asunto(s)
Inmunidad Innata/inmunología , Linfocitos/inmunología , Células del Estroma/inmunología , Animales , Bronquios/inmunología , Citocinas/inmunología , Interleucina-13/inmunología , Interleucina-33/inmunología , Ratones , Linfocitos T Reguladores/inmunología , Células Th2/inmunología , Linfopoyetina del Estroma TímicoRESUMEN
Food allergy is classically characterized by an inappropriate type-2 immune response to allergenic food antigens. However, how allergens are detected and how that detection leads to the initiation of allergic immunity is poorly understood. In addition to the gastrointestinal tract, the barrier epithelium of the skin may also act as a site of food allergen sensitization. These barrier epithelia are densely innervated by sensory neurons, which respond to diverse physical environmental stimuli. Recent findings suggest that sensory neurons can directly detect a broad array of immunogens, including allergens, triggering sensory responses and the release of neuropeptides that influence immune cell function. Reciprocally, immune mediators modulate the activation or responsiveness of sensory neurons, forming neuroimmune feedback loops that may impact allergic immune responses. By utilizing cutaneous allergen exposure as a model, this review explores the pivotal role of sensory neurons in allergen detection and their dynamic bidirectional communication with the immune system, which ultimately orchestrates the type-2 immune response. Furthermore, it sheds light on how peripheral signals are integrated within the central nervous system to coordinate hallmark features of allergic reactions. Drawing from this emerging evidence, we propose that atopy arises from a dysregulated neuroimmune circuit.
RESUMEN
In the small intestine, type 2 responses are regulated by a signaling circuit that involves tuft cells and group 2 innate lymphoid cells (ILC2s). Here, we identified the microbial metabolite succinate as an activating ligand for small intestinal (SI) tuft cells. Sequencing analyses of tuft cells isolated from the small intestine, gall bladder, colon, thymus, and trachea revealed that expression of tuft cell chemosensory receptors is tissue specific. SI tuft cells expressed the succinate receptor (SUCNR1), and providing succinate in drinking water was sufficient to induce a multifaceted type 2 immune response via the tuft-ILC2 circuit. The helminth Nippostrongylus brasiliensis and a tritrichomonad protist both secreted succinate as a metabolite. In vivo sensing of the tritrichomonad required SUCNR1, whereas N. brasiliensis was SUCNR1 independent. These findings define a paradigm wherein tuft cells monitor microbial metabolites to initiate type 2 immunity and suggest the existence of other sensing pathways triggering the response to helminths.
Asunto(s)
Inmunidad Mucosa/efectos de los fármacos , Mucosa Intestinal/citología , Mucosa Intestinal/inmunología , Receptores Acoplados a Proteínas G/metabolismo , Transducción de Señal/efectos de los fármacos , Ácido Succínico/farmacología , Animales , Línea Celular , Femenino , Mucosa Intestinal/metabolismo , Intestino Delgado/efectos de los fármacos , Intestino Delgado/inmunología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Nippostrongylus/efectos de los fármacos , Nippostrongylus/inmunología , Nippostrongylus/metabolismo , Especificidad de Órganos , Infecciones por Protozoos/inmunología , Receptores Acoplados a Proteínas G/inmunología , Transducción de Señal/inmunología , Especificidad de la Especie , Infecciones por Strongylida/inmunología , Canales Catiónicos TRPM/metabolismo , Células Th2/inmunología , Tritrichomonas/efectos de los fármacos , Tritrichomonas/inmunología , Tritrichomonas/metabolismoRESUMEN
The local regulation of type 2 immunity relies on dialog between the epithelium and the innate and adaptive immune cells. Here we found that alarmin-induced expression of the co-stimulatory molecule OX40L on group 2 innate lymphoid cells (ILC2s) provided tissue-restricted T cell co-stimulation that was indispensable for Th2 and regulatory T (Treg) cell responses in the lung and adipose tissue. Interleukin (IL)-33 administration resulted in organ-specific surface expression of OX40L on ILC2s and the concomitant expansion of Th2 and Treg cells, which was abolished upon deletion of OX40L on ILC2s (Il7raCre/+Tnfsf4fl/fl mice). Moreover, Il7raCre/+Tnfsf4fl/fl mice failed to mount effective Th2 and Treg cell responses and corresponding adaptive type 2 pulmonary inflammation arising from Nippostrongylus brasiliensis infection or allergen exposure. Thus, the increased expression of OX40L in response to IL-33 acts as a licensing signal in the orchestration of tissue-specific adaptive type 2 immunity, without which this response fails to establish.