The renaissance of oral tolerance: merging tradition and new insights

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. Oral tolerance describes how the oral administration of harmless antigens (such as dietary proteins) leads to systemic immune unresponsiveness to these antigens. Its failure can lead to conditions such as food allergies. This Review from Cerovic, Pabst and Mowat explores new insights into the mechanisms of oral tolerance, discussing how ingested antigens enter and are processed in the intestine, the roles for unique antigen-presenting cells and the induction of immunosuppressive T cell populations. The authors also examine the maintenance of tolerance to bacterial antigens in the intestine, and they discuss the mechanisms behind the failure of oral tolerance and potential clinical interventions.