An Impressive Example of Peripheral Tolerance Against Nonself: Tolerance to Commensal Bacterial and Dietary Protein Antigens

Abstract

This chapter deals with commensal bacteria and dietary proteins which can be regarded as typical examples of well-tolerated nonself. The specific unresponsiveness to commensal bacteria together with tolerance induction to dietary proteins is subsumed under the phenomenon of oral tolerance to nonself that can be regarded as an expression of peripheral tolerance. Several suppressive principles of the host have been identified to protect commensal microorganisms including interleukin-10, IgA antibodies, innate lymphocytes such as gammadelta T cells, and distinct gut-resident Foxp3⁺ regulatory T cells. Whereas peripheral regulatory T cells in other organs have T cell receptors specific for self antigens, intestinal regulatory T cells have a distinct set of T cell receptors that are specific for intestinal harmless microbial and dietary nonself antigens. The differentiation, migration, accumulation, and maintenance of intestinal regulatory T cells are promoted by both specialized intestinal dendritic cells and specific signals from the local environment, including individual members of the microbiota such as Clostridia species. It has been becoming increasingly apparent that the superstruction of intestinal tolerance to microbial antigens derived from commensals and dietary antigens derived from ingested food reflects considerable complexity. Understanding the development and the maintenance of intestinal regulatory T cells provides valuable insights into both intestinal homeostasis of the host and disease-relevant host-microbe interactions.