Every day the intestine is exposed to foreign antigenic material from the consumption of food. The intestine is also colonized with a dense community of commensal microbes, which are also foreign, referred to as the microbiota. All of this foreign material finds itself in the gastrointestinal tract where only a thin single cell layer of epithelial cells is the barrier between self and non-self. Thus, the intestinal immune system has to discriminate between generating protective immunity against harmful antigens and tolerance against harmless materials.(Weiner, Cunha et al. 2005; Pabst and Mowat 2012)
Active immune responses directed against the microbiota can result in inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis. Failure to induce tolerance to food protein is thought to result in food allergy and celiac disease(Stamnaes and Sollid 2015), which is the most prevalent food-induced pathology.
The ability of orally administered antigen to suppress subsequent immune responses, both in the gut and in the systemic immune system is referred to as “oral tolerance”. Tolerance to food protein induced via the small intestine affects local and systemic immune responses; tolerance to gut bacteria in the colon does not reduce systemic responses.(Pabst and Mowat 2012) Oral tolerance is often used interchangeably to describe tolerance to food protein and bacteria, however, experts believe that this arbitrary terminology is potentially misleading.
While the gut microbiota and their metabolites impact host immunity,(Rooks and Garrett 2016; Kim, Zeng et al. 2017) this review will focus on “oral tolerance” which will be used to describe tolerance to orally administered soluble antigens that influences mucosally induced tolerance that can be induced by other antigens in different parts of the intestine.
Gut-associated lymphoid tissue (GALT) found in the small intestine epithelium includes Peyer’s patches, isolated lymphoid follicles and microfold cells (M-cells) which mediate transcellular transport of particulate material including intestinal microbiota.(Fagarasan and Honjo 2003; Pabst and Mowat 2012)
Antigens that pass through the intestinal villous M-cells are passed on to lymphocytes called antigen-presenting dendritic cells (DCs) that reside just below the M-cells or in a “pocket” created at the basolateral surface of the M-cell. Upon exposure to the particulate matter, surrounding epithelial cells can attract more DCs via their production of CCL20 which can attract more DCs via their expression of a chemokine receptor (CCR6). Expression of CCR6, activates pathogen-specific T cells in Peyer’s patches.(Salazar-Gonzalez, Niess et al. 2006)
Pathogenic bacteria and dead cells are internalized by a unique subset of Peyer’s patch dendritic cells that express lysozyme. (Lelouard, Henri et al. 2010)Specialized retinoic acid-dependent(Weiner, Cunha et al. 2005) DC’s (CD103+) in the lamina propria underlying the normal villus epithelium also plays a critical role in presenting antigen for the induction of tolerance. The CD103+ DC’s may acquire soluble antigens that diffuse through the tight junctions between epithelial villus cells or that have transferred across epithelial cells by passing through the villus by transcellular mechanisms.
Cell-derived vesicles called exosomes containing antigen derived from class II MHC+ enterocytes may be taken up by DCs. In addition, specialized macrophages (CX3CR1) have also been reported to capture luminal antigens by extending processes through the epithelial layer and then passing them on to neighboring CD103+ DCs. The antigen presenting cells are very important in stimulating a balanced immune response such as removal of harmful pathogens versus induction of tolerance to beneficial bacteria and to non-pathogenic environmental and dietary antigens.