RESUMO
Genome-wide association studies have identified risk loci associated with the development of inflammatory bowel disease, while epidemiological studies have emphasized that pathogenesis likely involves host interactions with environmental elements whose source and structure need to be defined. Here, we identify a class of compounds derived from dietary, microbial, and industrial sources that are characterized by the presence of a five-membered oxazole ring and induce CD1d-dependent intestinal inflammation. We observe that minimal oxazole structures modulate natural killer T cell-dependent inflammation by regulating lipid antigen presentation by CD1d on intestinal epithelial cells (IECs). CD1d-restricted production of interleukin 10 by IECs is limited through activity of the aryl hydrocarbon receptor (AhR) pathway in response to oxazole induction of tryptophan metabolites. As such, the depletion of the AhR in the intestinal epithelium abrogates oxazole-induced inflammation. In summary, we identify environmentally derived oxazoles as triggers of CD1d-dependent intestinal inflammatory responses that occur via activation of the AhR in the intestinal epithelium.
Assuntos
Colite/patologia , Dieta , Intestinos/patologia , Oxazóis/farmacologia , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Antígenos CD1d/genética , Antígenos CD1d/metabolismo , Colite/induzido quimicamente , Colite/metabolismo , Modelos Animais de Doenças , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Interleucina-10/metabolismo , Intestinos/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células T Matadoras Naturais/imunologia , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptores de Hidrocarboneto Arílico/antagonistas & inibidores , Receptores de Hidrocarboneto Arílico/genética , Triptofano/metabolismoRESUMO
Coevolution of beneficial microorganisms with the mammalian intestine fundamentally shapes mammalian physiology. Here, we report that the intestinal microbe Bacteroides fragilis modifies the homeostasis of host invariant natural killer T (iNKT) cells by supplementing the host's endogenous lipid antigen milieu with unique inhibitory sphingolipids. The process occurs early in life and effectively impedes iNKT cell proliferation during neonatal development. Consequently, total colonic iNKT cell numbers are restricted into adulthood, and hosts are protected against experimental iNKT cell-mediated, oxazolone-induced colitis. In studies with neonatal mice lacking access to bacterial sphingolipids, we found that treatment with B. fragilis glycosphingolipids-exemplified by an isolated peak (MW = 717.6) called GSL-Bf717-reduces colonic iNKT cell numbers and confers protection against oxazolone-induced colitis in adulthood. Our results suggest that the distinctive inhibitory capacity of GSL-Bf717 and similar molecules may prove useful in the treatment of autoimmune and allergic disorders in which iNKT cell activation is destructive.
Assuntos
Bacteroides fragilis/metabolismo , Colite/imunologia , Glicoesfingolipídeos/metabolismo , Células T Matadoras Naturais/imunologia , Animais , Animais Recém-Nascidos , Proliferação de Células , Colite/induzido quimicamente , Colite/prevenção & controle , Colo/crescimento & desenvolvimento , Colo/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Células T Matadoras Naturais/citologia , OxazolonaRESUMO
The traditional view of immune cells is that their role within the body is to combat infections; however, it is becoming increasingly clear that they also perform tasks that are not classically associated with inflammation and pathogen clearance. These functions are executed deep within tissues, which are often poorly accessible and subject to environmental variability, especially in humans. Here, we discuss how multicellular 3D systems in a dish - organoids - are transitioning from a proof-of-principle approach to a timely, robust and reliable tool. Although we primarily focus on recent findings enabled by intestinal organoids co-cultured with lymphocytes, we posit that organoid co-culture systems will support future efforts to disentangle the interactions between a plethora of different cell types throughout development, homeostasis, regeneration and disease.
Assuntos
Intestinos , Organoides , Técnicas de Cocultura , Humanos , Células-TroncoRESUMO
The intestine hosts the largest immune cell compartment in the body as a result of its continuous exposure to exogenous antigens. The intestinal barrier is formed by a single layer of epithelial cells which separate immune cells from the gut lumen. Bidirectional interactions between the epithelium and the immune compartment are critical for maintaining intestinal homeostasis by limiting infection, preventing excessive immune activation, and promoting tissue repair processes. However, our understanding of epithelial-immune interactions incomplete as the complexity of in vivo models can hinder mechanistic studies, cell culture models lack the cellular heterogeneity of the intestine and when established from primary cell can be difficult to maintain. In the last decade, organoids have emerged as a reliable model of the intestine, recapitulating key cellular and architectural features of native tissues. Herein, we provide an overview of how intestinal organoids are being co-cultured with immune cells leading to substantial advances in our understanding of immune-epithelial interactions in the gut. This has enabled new discoveries of the immune contribution to epithelial maintenance and regeneration both in homeostasis and in disease such as chronic inflammation, infection and cancer. Organoids can additionally be used to generate immune cells with a tissue-specific phenotype and to investigate the impact of disease associated risk genes on the intestinal immune environment. Accordingly, this review demonstrates the multitude of applications for intestinal organoids in immunological research and their potential for translational approaches.
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T-bet is the lineage-specifying transcription factor for CD4+ TH 1 cells. T-bet has also been found in other CD4+ T cell subsets, including TH 17 cells and Treg, where it modulates their functional characteristics. However, we lack information on when and where T-bet is expressed during T cell differentiation and how this impacts T cell differentiation and function. To address this, we traced the ontogeny of T-bet-expressing cells using a fluorescent fate-mapping mouse line. We demonstrate that T-bet is expressed in a subset of CD4+ T cells that have naïve cell surface markers and transcriptional profile and that this novel cell population is phenotypically and functionally distinct from previously described populations of naïve and memory CD4+ T cells. Naïve-like T-bet-experienced cells are polarized to the TH 1 lineage, predisposed to produce IFN-γ upon cell activation, and resist repolarization to other lineages in vitro and in vivo. These results demonstrate that lineage-specifying factors can polarize T cells in the absence of canonical markers of T cell activation and that this has an impact on the subsequent T-helper response.
Assuntos
Proteínas com Domínio T , Células Th1 , Animais , Diferenciação Celular , Regulação da Expressão Gênica , Ativação Linfocitária , Camundongos , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Linfócitos T Reguladores/metabolismo , Células Th17/metabolismo , Células Th2RESUMO
Innate lymphoid cells are central to the regulation of immunity at mucosal barrier sites, with group 2 innate lymphoid cells (ILC2s) being particularly important in type 2 immunity. In this study, we demonstrate that microRNA(miR)-142 plays a critical, cell-intrinsic role in the homeostasis and function of ILC2s. Mice deficient for miR-142 expression demonstrate an ILC2 progenitor-biased development in the bone marrow, and along with peripheral ILC2s at mucosal sites, these cells display a greatly altered phenotype based on surface marker expression. ILC2 proliferative and effector functions are severely dysfunctional following Nippostrongylus brasiliensis infection, revealing a critical role for miR-142 isoforms in ILC2-mediated immune responses. Mechanistically, Socs1 and Gfi1 expression are regulated by miR-142 isoforms in ILC2s, impacting ILC2 phenotypes as well as the proliferative and effector capacity of these cells. The identification of these novel pathways opens potential new avenues to modulate ILC2-dependent immune functions.
Assuntos
Linfócitos/imunologia , MicroRNAs/imunologia , Animais , Células HEK293 , Homeostase , Humanos , Imunidade Inata/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/genéticaRESUMO
Organoids can shed light on the dynamic interplay between complex tissues and rare cell types within a controlled microenvironment. Here, we develop gut organoid cocultures with type-1 innate lymphoid cells (ILC1) to dissect the impact of their accumulation in inflamed intestines. We demonstrate that murine and human ILC1 secrete transforming growth factor ß1, driving expansion of CD44v6+ epithelial crypts. ILC1 additionally express MMP9 and drive gene signatures indicative of extracellular matrix remodelling. We therefore encapsulated human epithelial-mesenchymal intestinal organoids in MMP-sensitive, synthetic hydrogels designed to form efficient networks at low polymer concentrations. Harnessing this defined system, we demonstrate that ILC1 drive matrix softening and stiffening, which we suggest occurs through balanced matrix degradation and deposition. Our platform enabled us to elucidate previously undescribed interactions between ILC1 and their microenvironment, which suggest that they may exacerbate fibrosis and tumour growth when enriched in inflamed patient tissues.
Assuntos
Matriz Extracelular/metabolismo , Mucosa Intestinal/metabolismo , Linfócitos/metabolismo , Organoides/metabolismo , Animais , Feminino , Humanos , Mucosa Intestinal/citologia , Linfócitos/citologia , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Organoides/citologia , Fator de Crescimento Transformador beta1/metabolismoRESUMO
The production of cytokines such as interferon-gamma and interleukin 17 by alphabeta and gammadelta T cells influences the outcome of immune responses. Here we show that most gammadelta T lymphocytes expressed the tumor necrosis factor receptor family member CD27 and secreted interferon-gamma, whereas interleukin 17 production was restricted to CD27(-) gammadelta T cells. In contrast to the apparent plasticity of alphabeta T cells, the cytokine profiles of these distinct gammadelta T cell subsets were essentially stable, even during infection. These phenotypes were established during thymic development, when CD27 functions as a regulator of the differentiation of gammadelta T cells at least in part by inducing expression of the lymphotoxin-beta receptor and genes associated with trans-conditioning and interferon-gamma production. Thus, the cytokine profiles of peripheral gammadelta T cells are predetermined mainly by a mechanism involving CD27.
Assuntos
Interferon gama/imunologia , Interleucina-17/imunologia , Células Progenitoras Linfoides/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Subpopulações de Linfócitos T/imunologia , Timo/imunologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia , Animais , Ligante CD27/imunologia , Células Cultivadas , Receptor beta de Linfotoxina/imunologia , Malária Cerebral/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Plasmodium berghei , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/genéticaRESUMO
The mechanisms by which mucosal homeostasis is maintained are of central importance to inflammatory bowel disease. Critical to these processes is the intestinal epithelial cell (IEC), which regulates immune responses at the interface between the commensal microbiota and the host. CD1d presents self and microbial lipid antigens to natural killer T (NKT) cells, which are involved in the pathogenesis of colitis in animal models and human inflammatory bowel disease. As CD1d crosslinking on model IECs results in the production of the important regulatory cytokine interleukin (IL)-10 (ref. 9), decreased epithelial CD1d expression--as observed in inflammatory bowel disease--may contribute substantially to intestinal inflammation. Here we show in mice that whereas bone-marrow-derived CD1d signals contribute to NKT-cell-mediated intestinal inflammation, engagement of epithelial CD1d elicits protective effects through the activation of STAT3 and STAT3-dependent transcription of IL-10, heat shock protein 110 (HSP110; also known as HSP105), and CD1d itself. All of these epithelial elements are critically involved in controlling CD1d-mediated intestinal inflammation. This is demonstrated by severe NKT-cell-mediated colitis upon IEC-specific deletion of IL-10, CD1d, and its critical regulator microsomal triglyceride transfer protein (MTP), as well as deletion of HSP110 in the radioresistant compartment. Our studies thus uncover a novel pathway of IEC-dependent regulation of mucosal homeostasis and highlight a critical role of IL-10 in the intestinal epithelium, with broad implications for diseases such as inflammatory bowel disease.
Assuntos
Antígenos CD1d/imunologia , Células Epiteliais/imunologia , Imunidade nas Mucosas/imunologia , Interleucina-10/imunologia , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Animais , Proteínas de Transporte/metabolismo , Colite/imunologia , Colite/patologia , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Feminino , Proteínas de Choque Térmico HSP110/genética , Proteínas de Choque Térmico HSP110/metabolismo , Humanos , Inflamação/imunologia , Inflamação/patologia , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/patologia , Interleucina-10/genética , Masculino , Camundongos , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/metabolismo , Oxazolona , Fator de Transcrição STAT3/metabolismoRESUMO
OBJECTIVES: Recent experimental evidence suggests that environmental microbial factors early in life determine susceptibility to allergic diseases through inappropriate chemotaxis and local activation of CD1d-restricted, invariant chain natural killer T (iNKT) cells. In this study, we analyzed the involvement of these pathways in pediatric patients with eosinophilic esophagitis (EoE) before and after dietary allergen elimination. METHODS: mRNA expression levels of components of the C-X-C motif chemokine ligand 16 (CXCL16)-iNKT-CD1d axis were compared in esophageal biopsies from EoE patients vs. normal or inflammatory controls and before and after treatment. RESULTS: CXCL16, iNKT cell-associated cell marker Vα24, and CD1d were significantly upregulated in esophageal biopsies from EoE patients and correlated with the expression of inflammatory mediators associated with allergy. Upregulation of each of these factors was significantly more pronounced in patients aged <6 years at diagnosis, and this early-onset EoE subpopulation was characterized by a more prominent food allergic disease phenotype in a cohort-wide analysis. Successful, but not unsuccessful, treatment of early-onset EoE patients with dietary elimination of instigating allergens led to reduction in infiltrating iNKT cells and complete normalization of mRNA expression levels of CXCL16 and CD1d. CONCLUSIONS: Our observations place iNKT cells at the center of allergic inflammation associated with EoE, which could have profound implications for our understanding, treatment and prevention of this and other human allergic diseases.
Assuntos
Antígenos CD1d/metabolismo , Quimiocinas CXC/metabolismo , Dietoterapia , Esofagite Eosinofílica/imunologia , Esôfago/imunologia , Hipersensibilidade Alimentar/imunologia , Células T Matadoras Naturais/metabolismo , Receptores Depuradores/metabolismo , Adolescente , Idade de Início , Biomarcadores/metabolismo , Biópsia , Quimiocina CXCL16 , Quimiotaxia , Criança , Pré-Escolar , Esofagite Eosinofílica/dietoterapia , Esofagite Eosinofílica/patologia , Esôfago/patologia , Feminino , Hipersensibilidade Alimentar/dietoterapia , Hipersensibilidade Alimentar/patologia , Humanos , Lactente , Modelos Logísticos , Estudos Longitudinais , Masculino , Análise Multivariada , Fenótipo , Estudos Prospectivos , Resultado do Tratamento , Regulação para CimaRESUMO
The prevalence and incidence of chronic inflammatory disorders, including allergies and asthma, as well as inflammatory bowel disease, remain on the increase. Microbes are among the environmental factors that play an important role in shaping normal and pathologic immune responses. Several concepts have been put forward to explain the effect of microbes on the development of these conditions, including the hygiene hypothesis and the microbiota hypothesis. Recently, the dynamics of the development of (intestinal) microbial colonization, its effect on innate and adaptive immune responses (homeostasis), and the role of environmental factors, such as nutrition and others, have been extensively investigated. Furthermore, there is now increasing evidence that a qualitative and quantitative disturbance in colonization (dysbiosis) is associated with dysfunction of immune responses and development of various chronic inflammatory disorders. In this article the recent epidemiologic, clinical, and experimental evidence for this interaction is discussed.
Assuntos
Inflamação/imunologia , Inflamação/microbiologia , Metagenoma , Animais , Biodiversidade , Trato Gastrointestinal/imunologia , Trato Gastrointestinal/microbiologia , Humanos , Hipótese da Higiene , Hipersensibilidade/imunologia , Hipersensibilidade/microbiologia , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/microbiologiaRESUMO
The intestine performs functions central to human health by breaking down food and absorbing nutrients while maintaining a selective barrier against the intestinal microbiome. Key to this barrier function are the combined efforts of lumen-lining specialized intestinal epithelial cells, and the supportive underlying immune cell-rich stromal tissue. The discovery that the intestinal epithelium can be reproduced in vitro as intestinal organoids introduced a new way to understand intestinal development, homeostasis, and disease. However, organoids reflect the intestinal epithelium in isolation whereas the underlying tissue also contains myriad cell types and impressive chemical and structural complexity. This review dissects the cellular and matrix components of the intestine and discusses strategies to replicate them in vitro using principles drawing from bottom-up biological self-organization and top-down bioengineering. It also covers the cellular, biochemical and biophysical features of the intestinal microenvironment and how these can be replicated in vitro by combining strategies from organoid biology with materials science. Particularly accessible chemistries that mimic the native extracellular matrix are discussed, and bioengineering approaches that aim to overcome limitations in modelling the intestine are critically evaluated. Finally, the review considers how further advances may extend the applications of intestinal models and their suitability for clinical therapies.
Assuntos
Bioengenharia , Mucosa Intestinal , Humanos , Organoides/metabolismo , Engenharia Biomédica , Células Epiteliais/metabolismoRESUMO
PURPOSE OF REVIEW: Recognition of the importance of innate lymphoid cells (ILCs) in the immune mechanisms of food allergy has grown in recent years. This review summarizes recent findings of ILCs in immunoglobulin E (IgE)-mediated food allergy. New research on ILCs in the context of the microbiome and other atopic diseases are also considered with respect to how they can inform understanding of the role of ILCs in food allergy. RECENT FINDINGS: ILCs can mediate allergic and tolerogenic responses through multiple pathways. A novel subset of interleukin (IL)-10 producing ILC2s are associated with tolerance following immunotherapy to grass pollen, house dust mite allergy and lipid transfer protein allergy. ILC2s can drive food allergen-specific T cell responses in an antigen-specific manner. A memory subset of ILC2s has been identified through studies of other atopic diseases and is associated with effectiveness of response to therapy. SUMMARY: The role of ILCs in food allergy and oral tolerance is relatively understudied compared to other diseases. ILCs can modulate immune responses through several mechanisms, and it is likely that these are of importance in the context of food allergy. Better understanding of theses pathways may help to answer fundamental questions regarding the development of food allergy and lead to novel therapeutic targets and treatment.
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Type-3 innate lymphoid cells (ILC3) respond to localized environmental cues to regulate homeostasis and orchestrate immunity in the intestine. The intestinal epithelium is an important upstream regulator and downstream target of ILC3 signaling, however, the complexity of mucosal tissues can hinder efforts to define specific interactions between these two compartments. Here, we employ a reductionist co-culture system of murine epithelial small intestinal organoids (SIO) with ILC3 to uncover bi-directional signaling mechanisms that underlie intestinal homeostasis. We report that ILC3 induce global transcriptional changes in intestinal epithelial cells, driving the enrichment of secretory goblet cell signatures. We find that SIO enriched for goblet cells promote NKp46+ ILC3 and interleukin (IL)-22 expression, which can feedback to induce IL-22-mediated epithelial transcriptional signatures. However, we show that epithelial regulation of ILC3 in this system is contact-dependent and demonstrate a role for epithelial Delta-Like-Canonical-Notch-Ligand (Dll) in driving IL-22 production by ILC3, via subset-specific Notch1-mediated activation of T-bet+ ILC3. Finally, by interfering with Notch ligand-receptor dynamics, ILC3 appear to upregulate epithelial Atoh1 to skew secretory lineage determination in SIO-ILC3 co-cultures. This research outlines two complimentary bi-directional signaling modules between the intestinal epithelium and ILC3, which may be relevant in intestinal homeostasis and disease.
Assuntos
Interleucina 22 , Linfócitos , Camundongos , Animais , Imunidade Inata , Ligantes , Mucosa Intestinal , Receptores Notch/metabolismoRESUMO
Huge progress has been made in understanding the biology of innate lymphoid cells (ILC) by adopting several well-known concepts in T cell biology. As such, flow cytometry gating strategies and markers, such as CD90, have been applied to indentify ILC. Here, we report that most non-NK intestinal ILC have a high expression of CD90 as expected, but surprisingly a sub-population of cells exhibit low or even no expression of this marker. CD90-negative and CD90-low CD127+ ILC were present amongst all ILC subsets in the gut. The frequency of CD90-negative and CD90-low CD127+ ILC was dependent on stimulatory cues in vitro and enhanced by dysbiosis in vivo. CD90-negative and CD90-low CD127+ ILC were a potential source of IL-13, IFNγ and IL-17A at steady state and upon dysbiosis- and dextran sulphate sodium-elicited colitis. Hence, this study reveals that, contrary to expectations, CD90 is not constitutively expressed by functional ILC in the gut.
Assuntos
Colite , Imunidade Inata , Humanos , Colite/metabolismo , Citocinas/metabolismo , Disbiose/metabolismo , Linfócitos/metabolismo , Antígenos Thy-1/imunologiaRESUMO
γδ T cells are increasingly recognized as having important functional roles in a range of disease scenarios such as infection, allergy, autoimmunity and cancer. With this has come realization that γδ cells are not a homogeneous population of cells with a single physiological role. Instead, ever increasing complexity in both phenotype and function is being ascribed to γδ cell subsets from various tissues and locations, and in both mouse and human. Here, we review this complexity by describing how diverse γδ cell subsets are generated in the murine thymus, and how these events relate to subsequent γδ subset function in the periphery. We then review the two major γδ cell populations in human, highlighting the several similarities of Vδ1(+) cells to certain murine γδ subsets, and describing the remarkable functional plasticity of human Vδ2(+) cells. A better understanding of this spectrum of γδ cell phenotypes should facilitate more targeted approaches to utilise their tremendous functional potential in the clinic.
Assuntos
Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Subpopulações de Linfócitos T/imunologia , Animais , Diferenciação Celular/imunologia , Linhagem da Célula/imunologia , Humanos , Ativação Linfocitária , Camundongos , Modelos Imunológicos , Transdução de Sinais/imunologia , Especificidade da Espécie , Subpopulações de Linfócitos T/citologia , Timo/citologia , Timo/imunologiaRESUMO
Inflammatory bowel disease (IBD) is an idiopathic condition characterized by chronic relapsing inflammation in the intestine. While the precise etiology of IBD remains unknown, genetics, the gut microbiome, environmental factors, and the immune system have all been shown to contribute to the disease pathophysiology. In recent years, attention has shifted towards the role that innate lymphoid cells (ILCs) may play in the dysregulation of intestinal immunity observed in IBD. ILCs are a group of heterogenous immune cells which can be found at mucosal barriers. They act as critical mediators of the regulation of intestinal homeostasis and the orchestration of its inflammatory response. Despite helper-like type 1 ILCs (ILC1s) constituting a particularly rare ILC population in the intestine, recent work has suggested that an accumulation of intestinal ILC1s in individuals with IBD may act to exacerbate its pathology. In this review, we summarize existing knowledge on helper-like ILC1 plasticity and their classification in murine and human settings. Moreover, we discuss what is currently understood about the roles that ILC1s may play in the progression of IBD pathogenesis.
Assuntos
Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Animais , Humanos , Imunidade Inata , Intestinos , Linfócitos , CamundongosRESUMO
Complex co-cultures of organoids with immune cells provide a versatile tool for interrogating the bi-directional interactions that underpin the delicate balance of mucosal homeostasis. These 3D, multi-cellular systems offer a reductionist model for addressing multi-factorial diseases and resolving technical difficulties that arise when studying rare cell types such as tissue-resident innate lymphoid cells (ILCs). This article describes a murine system that combines small intestine organoids and small intestine lamina propria derived helper-like type-1 ILCs (ILC1s), which can be readily extended to other ILC or immune populations. ILCs are a tissue-resident population that is particularly enriched in the mucosa, where they promote homeostasis and rapidly respond to damage or infection. Organoid co-cultures with ILCs have already begun shedding light on new epithelial-immune signaling modules in the gut, revealing how different ILC subsets impact intestinal epithelial barrier integrity and regeneration. This protocol will enable further investigations into reciprocal interactions between epithelial and immune cells, which hold the potential to provide new insights into the mechanisms of mucosal homeostasis and inflammation.
Assuntos
Imunidade Inata , Linfócitos , Animais , Técnicas de Cocultura , Intestino Delgado , Linfócitos/metabolismo , Camundongos , OrganoidesRESUMO
Organoid-based models of murine and human innate lymphoid cell precursor (ILCP) maturation are presented. First, murine intestinal and pulmonary organoids are harnessed to demonstrate that the epithelial niche is sufficient to drive tissue-specific maturation of all innate lymphoid cell (ILC) groups in parallel, without requiring subset-specific cytokine supplementation. Then, more complex human induced pluripotent stem cell (hiPSC)-based gut and lung organoid models are used to demonstrate that human epithelial cells recapitulate maturation of ILC from a stringent systemic human ILCP population, but only when the organoid-associated stromal cells are depleted. These systems offer versatile and reductionist models to dissect the impact of environmental and mucosal niche cues on ILC maturation. In the future, these could provide insight into how ILC activity and development might become dysregulated in chronic inflammatory diseases.