Mechanisms of Oral Tolerance

Abstract

Oral tolerance is a state of systemic unresponsiveness that is the default response to food antigens in the gastrointestinal tract, although immune tolerance can also be induced by other routes, such as the skin or inhalation. Antigen can be acquired directly by intestinal phagocytes, or pass through enterocytes or goblet cell-associated passages prior to capture by dendritic cells (DCs) in the lamina propria. Mucin from goblet cells acts on DCs to render them more tolerogenic. A subset of regulatory DCs expressing CD103 is responsible for delivery of antigen to the draining lymph node and induction of Tregs. These DCs also imprint gastrointestinal homing capacity, allowing the recently primed Tregs to home back to the lamina propria where they interact with macrophages that produce IL-10 and expand. Tregs induced by dietary antigen include Foxp3⁺ Tregs and Foxp3^- Tregs. In addition to Tregs, T cell anergy can also contribute to oral tolerance. The microbiota plays a key role in the development of oral tolerance, through regulation of macrophages and innate lymphoid cells that contribute to the regulatory phenotype of gastrointestinal dendritic cells. Absence of microbiota is associated with a susceptibility to food allergy, while presence of Clostridia strains can suppress development of food allergy through enhancement of Tregs and intestinal barrier function. It is not clear if feeding of antigens can also induce true immune tolerance after a memory immune response has been generated, but mechanistic studies of oral immunotherapy trials demonstrate shared pathways in oral tolerance and oral immunotherapy, with a role for Tregs and anergy. An important role for IgA and IgG antibodies in development of immune tolerance is also supported by studies of oral tolerance in humans. The elucidation of key pathways in oral tolerance could identify new strategies to increase efficacy of immunotherapy treatments for food allergy.

Keywords: Antigen-presenting cells; Food allergy; Immunotherapy; Microbiota; Oral tolerance; Regulatory T cells.

Figure 1. Transport of dietary antigen through the intestinal epithelium

Soluble antigen that reaches the small intestine is absorbed by enterocytes (transcellular route). Antigen is usually degraded into small peptides inside vesicles. Peptides can be loaded into MHC-II in endosomes and be released to be taken up by CD103⁺ DCs. Antigens with resistance to proteolysis can reach the basolateral membrane in an intact form. Inflammation increases permeability and paracellular transport of soluble antigen. Goblet cells absorb antigens through goblet cell-associated antigen passages for delivery to CD103⁺ DCs. CXC3R1+ macrophages extent their dendrites through the intestinal epithelium to sample antigen from the lumen, and transfer antigen to CD103⁺ for transport to the MLN. Particulate antigen, such as bacteria or virus, is taken up through M cells that overlie Peyer’s patches.

Figure 2. Mechanism of oral tolerance

Dietary antigen is transported to the MLN by CD103+ DCs, that express high levels of RALDH, IDO, and TGF- β, facilitating naïve T cells to differentiate to Tregs. Tregs express gut-homing markers CCR9 and α₄β₇, and migrate back to the lamina propria. There, expansion of Tregs is induced by high levels of IL-10 produced by macrophages. GM-CSF produced by ILC3 also contributes to homeostasis of Tregs, by acting on DCs and macrophages. GM-CSF production is dependent on microbiota signals, in a mechanism mediated by IL1-b production by macrophages. Absorbed antigen also reaches the liver through the portal vein, where it is presented by plasmacytoid DCs, that induce deletion of antigen-specific T cells. Deletion and anergy are also induced in the MLN in response to high dose of antigen.