Pub Date : 2024-09-18DOI: 10.1038/s41577-024-01076-8
Ludger Klein, Elisabetta Petrozziello
The extent of central T cell tolerance is determined by the diversity of self-antigens that developing thymocytes ‘see’ on thymic antigen-presenting cells (APCs). Here, focusing on insights from the past decade, we review the functional adaptations of medullary thymic epithelial cells, thymic dendritic cells and thymic B cells for the purpose of tolerance induction. Their distinct cellular characteristics range from unconventional phenomena, such as promiscuous gene expression or mimicry of peripheral cell types, to strategic positioning in distinct microenvironments and divergent propensities to preferentially access endogenous or exogenous antigen pools. We also discuss how ‘tonic’ inflammatory signals in the thymic microenvironment may extend the intrathymically visible ‘self’ to include autoantigens that are otherwise associated with highly immunogenic peripheral environments.
{"title":"Antigen presentation for central tolerance induction","authors":"Ludger Klein, Elisabetta Petrozziello","doi":"10.1038/s41577-024-01076-8","DOIUrl":"https://doi.org/10.1038/s41577-024-01076-8","url":null,"abstract":"<p>The extent of central T cell tolerance is determined by the diversity of self-antigens that developing thymocytes ‘see’ on thymic antigen-presenting cells (APCs). Here, focusing on insights from the past decade, we review the functional adaptations of medullary thymic epithelial cells, thymic dendritic cells and thymic B cells for the purpose of tolerance induction. Their distinct cellular characteristics range from unconventional phenomena, such as promiscuous gene expression or mimicry of peripheral cell types, to strategic positioning in distinct microenvironments and divergent propensities to preferentially access endogenous or exogenous antigen pools. We also discuss how ‘tonic’ inflammatory signals in the thymic microenvironment may extend the intrathymically visible ‘self’ to include autoantigens that are otherwise associated with highly immunogenic peripheral environments.</p>","PeriodicalId":19049,"journal":{"name":"Nature Reviews Immunology","volume":null,"pages":null},"PeriodicalIF":100.3,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-18DOI: 10.1038/s41577-024-01080-y
Matthew J. Sweet, Divya Ramnath, Amit Singhal, Ronan Kapetanovic
Macrophages destroy bacteria and other microorganisms through phagocytosis-coupled antimicrobial responses, such as the generation of reactive oxygen species and the delivery of hydrolytic enzymes from lysosomes to the phagosome. However, many intracellular bacteria subvert these responses, escaping to other cellular compartments to survive and/or replicate. Such bacterial subversion strategies are countered by a range of additional direct antibacterial responses that are switched on by pattern-recognition receptors and/or host-derived cytokines and other factors, often through inducible gene expression and/or metabolic reprogramming. Our understanding of these inducible antibacterial defence strategies in macrophages is rapidly evolving. In this Review, we provide an overview of the broad repertoire of antibacterial responses that can be engaged in macrophages, including LC3-associated phagocytosis, metabolic reprogramming and antimicrobial metabolites, lipid droplets, guanylate-binding proteins, antimicrobial peptides, metal ion toxicity, nutrient depletion, autophagy and nitric oxide production. We also highlight key inducers, signalling pathways and transcription factors involved in driving these different antibacterial responses. Finally, we discuss how a detailed understanding of the molecular mechanisms of antibacterial responses in macrophages might be exploited for developing host-directed therapies to combat antibiotic-resistant bacterial infections.
{"title":"Inducible antibacterial responses in macrophages","authors":"Matthew J. Sweet, Divya Ramnath, Amit Singhal, Ronan Kapetanovic","doi":"10.1038/s41577-024-01080-y","DOIUrl":"https://doi.org/10.1038/s41577-024-01080-y","url":null,"abstract":"<p>Macrophages destroy bacteria and other microorganisms through phagocytosis-coupled antimicrobial responses, such as the generation of reactive oxygen species and the delivery of hydrolytic enzymes from lysosomes to the phagosome. However, many intracellular bacteria subvert these responses, escaping to other cellular compartments to survive and/or replicate. Such bacterial subversion strategies are countered by a range of additional direct antibacterial responses that are switched on by pattern-recognition receptors and/or host-derived cytokines and other factors, often through inducible gene expression and/or metabolic reprogramming. Our understanding of these inducible antibacterial defence strategies in macrophages is rapidly evolving. In this Review, we provide an overview of the broad repertoire of antibacterial responses that can be engaged in macrophages, including LC3-associated phagocytosis, metabolic reprogramming and antimicrobial metabolites, lipid droplets, guanylate-binding proteins, antimicrobial peptides, metal ion toxicity, nutrient depletion, autophagy and nitric oxide production. We also highlight key inducers, signalling pathways and transcription factors involved in driving these different antibacterial responses. Finally, we discuss how a detailed understanding of the molecular mechanisms of antibacterial responses in macrophages might be exploited for developing host-directed therapies to combat antibiotic-resistant bacterial infections.</p>","PeriodicalId":19049,"journal":{"name":"Nature Reviews Immunology","volume":null,"pages":null},"PeriodicalIF":100.3,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-17DOI: 10.1038/s41577-024-01079-5
Victor Bosteels, Sophie Janssens
Dendritic cells (DCs) are crucial gatekeepers of the balance between immunity and tolerance. They exist in two functional states, immature or mature, that refer to an information-sensing versus an information-transmitting state, respectively. Historically, the term DC maturation was used to describe the acquisition of immunostimulatory capacity by DCs following their triggering by pathogens or tissue damage signals. As such, immature DCs were proposed to mediate tolerance, whereas mature DCs were associated with the induction of protective T cell immunity. Later studies have challenged this view and unequivocally demonstrated that two distinct modes of DC maturation exist, homeostatic and immunogenic DC maturation, each with a distinct functional outcome. Therefore, the mere expression of maturation markers cannot be used to predict immunogenicity. How DCs become activated in homeostatic conditions and maintain tolerance remains an area of intense debate. Several recent studies have shed light on the signals driving the homeostatic maturation programme, especially in the conventional type 1 DC (cDC1) compartment. Here, we highlight our growing understanding of homeostatic DC maturation and the relevance of this process for immune tolerance.
树突状细胞(DC)是免疫与耐受之间平衡的关键守门人。它们有两种功能状态:未成熟或成熟,分别指信息感应状态和信息传递状态。历史上,DC 成熟一词被用来描述 DC 在被病原体或组织损伤信号触发后获得的免疫刺激能力。因此,人们认为未成熟的直流电介导耐受,而成熟的直流电则与诱导保护性 T 细胞免疫有关。后来的研究对这一观点提出了质疑,并明确表明存在两种不同的直流细胞成熟模式,即同源性直流细胞成熟和免疫原性直流细胞成熟,每种模式都有不同的功能结果。因此,不能仅凭成熟标志物的表达来预测免疫原性。DC 如何在平衡状态下被激活并维持耐受性仍是一个激烈争论的领域。最近的一些研究揭示了驱动平衡性成熟程序的信号,尤其是在传统的 1 型 DC(cDC1)中。在这里,我们将重点介绍我们对DC平衡性成熟以及这一过程与免疫耐受的相关性日益加深的认识。
{"title":"Striking a balance: new perspectives on homeostatic dendritic cell maturation","authors":"Victor Bosteels, Sophie Janssens","doi":"10.1038/s41577-024-01079-5","DOIUrl":"https://doi.org/10.1038/s41577-024-01079-5","url":null,"abstract":"<p>Dendritic cells (DCs) are crucial gatekeepers of the balance between immunity and tolerance. They exist in two functional states, immature or mature, that refer to an information-sensing versus an information-transmitting state, respectively. Historically, the term DC maturation was used to describe the acquisition of immunostimulatory capacity by DCs following their triggering by pathogens or tissue damage signals. As such, immature DCs were proposed to mediate tolerance, whereas mature DCs were associated with the induction of protective T cell immunity. Later studies have challenged this view and unequivocally demonstrated that two distinct modes of DC maturation exist, homeostatic and immunogenic DC maturation, each with a distinct functional outcome. Therefore, the mere expression of maturation markers cannot be used to predict immunogenicity. How DCs become activated in homeostatic conditions and maintain tolerance remains an area of intense debate. Several recent studies have shed light on the signals driving the homeostatic maturation programme, especially in the conventional type 1 DC (cDC1) compartment. Here, we highlight our growing understanding of homeostatic DC maturation and the relevance of this process for immune tolerance.</p>","PeriodicalId":19049,"journal":{"name":"Nature Reviews Immunology","volume":null,"pages":null},"PeriodicalIF":100.3,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-16DOI: 10.1038/s41577-024-01089-3
Alexandra Flemming
Starkl et al. show that mast cells have a key role in the metabolic network that underlies postoperative pain and demonstrate that this can be therapeutically targeted in mouse models.
{"title":"Mast cell BH4–serotonin metabolic network implicated in postoperative pain","authors":"Alexandra Flemming","doi":"10.1038/s41577-024-01089-3","DOIUrl":"https://doi.org/10.1038/s41577-024-01089-3","url":null,"abstract":"Starkl et al. show that mast cells have a key role in the metabolic network that underlies postoperative pain and demonstrate that this can be therapeutically targeted in mouse models.","PeriodicalId":19049,"journal":{"name":"Nature Reviews Immunology","volume":null,"pages":null},"PeriodicalIF":100.3,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142234452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-16DOI: 10.1038/s41577-024-01090-w
Francesca Di Rosa
Francesca Di Rosa works on T cells and is committed to science outreach. Together with Adrian Hayday, she recently conceptualized and delivered the exhibit ‘Vaccination, a time machine’ at the Royal Society Summer Exhibition in London. Here, she shares her thoughts on how to communicate a core scientific content with artistic and historical input, according to her ‘5C’ formula.
Francesca Di Rosa 从事 T 细胞研究,并致力于科学推广工作。最近,她与阿德里安-海岱(Adrian Hayday)一起,在伦敦皇家学会夏季展览上策划并举办了 "疫苗接种,时光机 "展览。在这里,她将根据自己的 "5C "公式,分享她对如何通过艺术和历史元素传播核心科学内容的看法。
{"title":"Using art and history to communicate immunology to a broad audience","authors":"Francesca Di Rosa","doi":"10.1038/s41577-024-01090-w","DOIUrl":"https://doi.org/10.1038/s41577-024-01090-w","url":null,"abstract":"Francesca Di Rosa works on T cells and is committed to science outreach. Together with Adrian Hayday, she recently conceptualized and delivered the exhibit ‘Vaccination, a time machine’ at the Royal Society Summer Exhibition in London. Here, she shares her thoughts on how to communicate a core scientific content with artistic and historical input, according to her ‘5C’ formula.","PeriodicalId":19049,"journal":{"name":"Nature Reviews Immunology","volume":null,"pages":null},"PeriodicalIF":100.3,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142235062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-10DOI: 10.1038/s41577-024-01073-x
Søren E. Degn, Pavel Tolar
Antibodies are exceptionally versatile molecules with remarkable flexibility in their binding properties. Their natural targets range from small-molecule toxins, across viruses of different sizes, to bacteria and large multicellular parasites. The molecular determinants bound by antibodies include proteins, peptides, carbohydrates, nucleic acids, lipids and even synthetic molecules that have never existed in nature. Membrane-anchored antibodies also serve as receptors on the surface of the B cells that produce them. Despite recent structural insights, there is still no unifying molecular mechanism to explain how antibody targets (antigens) trigger the activation of these B-cell receptors (BCRs). After cognate antigen encounter, somatic hypermutation and class-switch recombination allow BCR affinity maturation and immunoglobulin class-specific responses, respectively. This raises the fundamental question of how one receptor activation mechanism can accommodate a plethora of variant receptors and ligands, and how it can ensure that individual B cells remain responsive to antigen after somatic hypermutation and class switching. There is still no definite answer. Here we give a brief historical account of the different models proposed to explain BCR triggering and discuss their merit in the context of the current knowledge of the structure of BCRs, their dynamic membrane distribution, and recent biochemical and cell biological insights.
抗体是一种用途极为广泛的分子,其结合特性具有极大的灵活性。它们的天然靶标包括小分子毒素、不同大小的病毒、细菌和大型多细胞寄生虫。抗体结合的分子决定因素包括蛋白质、肽、碳水化合物、核酸、脂质,甚至是自然界从未存在过的合成分子。膜锚抗体也是产生抗体的 B 细胞表面的受体。尽管最近在结构上有了新的认识,但仍然没有统一的分子机制来解释抗体靶标(抗原)如何触发这些 B 细胞受体(BCR)的活化。在遇到同源抗原后,体细胞超突变和类开关重组分别使 BCR 亲和力成熟和产生免疫球蛋白类特异性反应。这就提出了一个根本性的问题:一种受体激活机制如何适应大量变异受体和配体,以及如何确保单个 B 细胞在体细胞超突变和类切换后仍能对抗原做出反应。目前还没有确切的答案。在此,我们简要介绍了为解释 BCR 触发而提出的不同模型的历史,并结合目前对 BCR 结构、其动态膜分布的了解以及最新的生化和细胞生物学见解,讨论了这些模型的优点。
{"title":"Towards a unifying model for B-cell receptor triggering","authors":"Søren E. Degn, Pavel Tolar","doi":"10.1038/s41577-024-01073-x","DOIUrl":"https://doi.org/10.1038/s41577-024-01073-x","url":null,"abstract":"<p>Antibodies are exceptionally versatile molecules with remarkable flexibility in their binding properties. Their natural targets range from small-molecule toxins, across viruses of different sizes, to bacteria and large multicellular parasites. The molecular determinants bound by antibodies include proteins, peptides, carbohydrates, nucleic acids, lipids and even synthetic molecules that have never existed in nature. Membrane-anchored antibodies also serve as receptors on the surface of the B cells that produce them. Despite recent structural insights, there is still no unifying molecular mechanism to explain how antibody targets (antigens) trigger the activation of these B-cell receptors (BCRs). After cognate antigen encounter, somatic hypermutation and class-switch recombination allow BCR affinity maturation and immunoglobulin class-specific responses, respectively. This raises the fundamental question of how one receptor activation mechanism can accommodate a plethora of variant receptors and ligands, and how it can ensure that individual B cells remain responsive to antigen after somatic hypermutation and class switching. There is still no definite answer. Here we give a brief historical account of the different models proposed to explain BCR triggering and discuss their merit in the context of the current knowledge of the structure of BCRs, their dynamic membrane distribution, and recent biochemical and cell biological insights.</p>","PeriodicalId":19049,"journal":{"name":"Nature Reviews Immunology","volume":null,"pages":null},"PeriodicalIF":100.3,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142160452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-09DOI: 10.1038/s41577-024-01075-9
Rebecca C. Coll, Kate Schroder
Inflammation drives pathology in many human diseases for which there are no disease-modifying drugs. Inflammasomes are signalling platforms that can induce pathological inflammation and tissue damage, having potential as an exciting new class of drug targets. Small-molecule inhibitors of the NLRP3 inflammasome that are now in clinical trials have demonstrated proof of concept that inflammasomes are druggable, and so drug development programmes are now focusing on other key inflammasome molecules. In this Review, we describe the potential of inflammasome components as candidate drug targets and the novel inflammasome inhibitors that are being developed. We discuss how the signalling biology of inflammasomes offers mechanistic insights for therapeutic targeting. We also discuss the major scientific and technical challenges associated with drugging these molecules during preclinical development and clinical trials.
{"title":"Inflammasome components as new therapeutic targets in inflammatory disease","authors":"Rebecca C. Coll, Kate Schroder","doi":"10.1038/s41577-024-01075-9","DOIUrl":"https://doi.org/10.1038/s41577-024-01075-9","url":null,"abstract":"<p>Inflammation drives pathology in many human diseases for which there are no disease-modifying drugs. Inflammasomes are signalling platforms that can induce pathological inflammation and tissue damage, having potential as an exciting new class of drug targets. Small-molecule inhibitors of the NLRP3 inflammasome that are now in clinical trials have demonstrated proof of concept that inflammasomes are druggable, and so drug development programmes are now focusing on other key inflammasome molecules. In this Review, we describe the potential of inflammasome components as candidate drug targets and the novel inflammasome inhibitors that are being developed. We discuss how the signalling biology of inflammasomes offers mechanistic insights for therapeutic targeting. We also discuss the major scientific and technical challenges associated with drugging these molecules during preclinical development and clinical trials.</p>","PeriodicalId":19049,"journal":{"name":"Nature Reviews Immunology","volume":null,"pages":null},"PeriodicalIF":100.3,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142160454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-09DOI: 10.1038/s41577-024-01085-7
Anne Spurkland
Anne Spurkland is a professor of medicine, and her research interests include T cell activation and autoimmunity. She is also an avid baker of cakes that everyone can have and eat too, irrespective of allergies and dietary preferences. This latter passion propelled her into national fame as one of Norway’s most visible experts on immunity and viruses during the COVID-19 pandemic.
安妮-斯伯克兰是医学教授,她的研究兴趣包括 T 细胞活化和自身免疫。她还热衷于制作蛋糕,让每个人都能吃到蛋糕,无论过敏与否。在 COVID-19 大流行期间,她是挪威最著名的免疫和病毒专家之一。
{"title":"Have a cake and eat it too: the importance of metaphors in research communication","authors":"Anne Spurkland","doi":"10.1038/s41577-024-01085-7","DOIUrl":"https://doi.org/10.1038/s41577-024-01085-7","url":null,"abstract":"Anne Spurkland is a professor of medicine, and her research interests include T cell activation and autoimmunity. She is also an avid baker of cakes that everyone can have and eat too, irrespective of allergies and dietary preferences. This latter passion propelled her into national fame as one of Norway’s most visible experts on immunity and viruses during the COVID-19 pandemic.","PeriodicalId":19049,"journal":{"name":"Nature Reviews Immunology","volume":null,"pages":null},"PeriodicalIF":100.3,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142160453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-06DOI: 10.1038/s41577-024-01077-7
Vuk Cerovic, Oliver Pabst, Allan McI Mowat
Oral tolerance is the process by which feeding of soluble proteins induces antigen-specific systemic immune unresponsiveness. Oral tolerance is thought to have a central role in suppressing immune responses to ‘harmless’ food antigens, and its failure can lead to development of pathologies such as food allergies or coeliac disease. However, on the basis of long-standing experimental observations, the relevance of oral tolerance in human health has achieved new prominence recently following the discovery that oral administration of peanut proteins prevents the development of peanut allergy in at-risk human infants. In this Review, we summarize the new mechanistic insights into three key processes necessary for the induction of tolerance to oral antigens: antigen uptake and transport across the small intestinal epithelial barrier to the underlying immune cells; the processing, transport and presentation of fed antigen by different populations of antigen-presenting cells; and the development of immunosuppressive T cell populations that mediate antigen-specific tolerance. In addition, we consider how related but distinct processes maintain tolerance to bacterial antigens in the large intestine. Finally, we outline the molecular mechanisms and functional consequences of failure of oral tolerance and how these may be modulated to enhance clinical outcomes and prevent disease.
口服耐受性是指通过喂食可溶性蛋白质诱导抗原特异性全身免疫无反应的过程。口腔耐受性被认为在抑制对 "无害 "食物抗原的免疫反应方面发挥着核心作用,如果口腔耐受性失效,就会导致食物过敏或乳糜泻等病症的发生。然而,在长期实验观察的基础上,口服耐受性与人类健康的相关性最近得到了新的重视,因为我们发现口服花生蛋白可防止高危婴儿发生花生过敏。在这篇综述中,我们总结了诱导对口服抗原产生耐受所必需的三个关键过程的新机理认识:抗原摄取和通过小肠上皮屏障转运至底层免疫细胞;不同的抗原呈递细胞群处理、转运和呈递喂养的抗原;以及介导抗原特异性耐受的免疫抑制 T 细胞群的发展。此外,我们还考虑了相关但不同的过程如何维持大肠对细菌抗原的耐受性。最后,我们概述了口腔耐受失败的分子机制和功能性后果,以及如何调节这些机制以提高临床疗效和预防疾病。
{"title":"The renaissance of oral tolerance: merging tradition and new insights","authors":"Vuk Cerovic, Oliver Pabst, Allan McI Mowat","doi":"10.1038/s41577-024-01077-7","DOIUrl":"https://doi.org/10.1038/s41577-024-01077-7","url":null,"abstract":"<p>Oral tolerance is the process by which feeding of soluble proteins induces antigen-specific systemic immune unresponsiveness. Oral tolerance is thought to have a central role in suppressing immune responses to ‘harmless’ food antigens, and its failure can lead to development of pathologies such as food allergies or coeliac disease. However, on the basis of long-standing experimental observations, the relevance of oral tolerance in human health has achieved new prominence recently following the discovery that oral administration of peanut proteins prevents the development of peanut allergy in at-risk human infants. In this Review, we summarize the new mechanistic insights into three key processes necessary for the induction of tolerance to oral antigens: antigen uptake and transport across the small intestinal epithelial barrier to the underlying immune cells; the processing, transport and presentation of fed antigen by different populations of antigen-presenting cells; and the development of immunosuppressive T cell populations that mediate antigen-specific tolerance. In addition, we consider how related but distinct processes maintain tolerance to bacterial antigens in the large intestine. Finally, we outline the molecular mechanisms and functional consequences of failure of oral tolerance and how these may be modulated to enhance clinical outcomes and prevent disease.</p>","PeriodicalId":19049,"journal":{"name":"Nature Reviews Immunology","volume":null,"pages":null},"PeriodicalIF":100.3,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142142437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}