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.

口服耐受是喂养可溶性蛋白质诱导抗原特异性全身免疫无反应的过程。口服耐受被认为在抑制对“无害”食物抗原的免疫反应方面发挥着核心作用，其失败可能导致食物过敏或乳糜泻等疾病的发生。然而，根据长期实验观察，口服耐受性与人类健康的相关性最近在发现口服花生蛋白可预防高危人类婴儿发生花生过敏后，得到了新的重视。在这篇综述中，我们总结了对诱导口服抗原耐受所需的三个关键过程的新机制见解：抗原的摄取和穿过小肠上皮屏障运输到潜在的免疫细胞；不同抗原呈递细胞群对饲喂抗原的加工、运输和呈递；以及介导抗原特异性耐受的免疫抑制性 T 细胞群的发展。此外，我们还考虑相关但不同的过程如何维持大肠中细菌抗原的耐受性。最后，我们概述了口服耐受失败的分子机制和功能后果，以及如何调节这些机制以增强临床结果和预防疾病。