Basic mechanisms and clinical implications of oral tolerance

Oral tolerance is the physiologic mechanism that prevents hypersensitivity to food proteins and probably to commensal bacteria. It has also attracted attention as a means of administering therapy for autoimmune and inflammatory diseases. Although evidence indicates that both clonal inactivation and active regulatory mechanisms may play a role and that the induction of these may be determined selectively by the feeding regimen used to induce tolerance, the exact mechanisms of oral tolerance remain unclear. Here, we discuss recent evidence that fed antigens are presented to CD4(+) T cells by antigen-presenting cells (APCs) that lack costimulatory activity, resulting in partial activation of T cells followed by a state of unresponsiveness. This seems to occur in many tissues of the immune system but may be particularly important in the draining mesenteric lymph node. Resting dendritic cells may be the predominant population of APCs involved in oral tolerance, and conditions that activate dendritic cells allow the induction of productive immunity. Conventionally, presentation of antigen in the absence of costimulation is thought to induce T-cell anergy, but evidence now indicates that anergic T cells can also act as regulatory cells via the production of inhibitory mediators or via cognate interactions with APCs and other T cells. We discuss how an ability to deactivate APCs may explain bystander suppressor activity in oral tolerance, and we consider how the production of transforming growth factor-beta or interleukin-10 by Th3 or T regulatory 1 cells may contribute to tolerance in vivo. We speculate that both the production of inhibitory mediators and the delivery of suppression via cognate interactions may be properties of otherwise "anergic" T cells.