The host is continuously exposed to the external environment via a large surface area covered by mucosal epithelium. The surface area of human mucosa is as much as 400m², or nearly equivalent to the surface of 1.5 tennis courts including oral cavity, nasal passage, digestive tract, respiratory apparatus, urinary tissue and reproductive organ. Enormous numbers of commensal bacteria colonize symbiotically on the large mucosal surface by creating appropriate homeostatic conditions. The mucosal immune system may be exercising quiescent immunological conditions by identifying these symbiotic microbiota as pseudo-selves. In this review, we first provide an outline of the uniqueness of the mucosal immune system represented by secretory IgA (S-IgA), intraepithelial lymphocyte (IEL) and oral tolerance. Then we introduce the latest insights concerning the symbiotic interaction between the mucosal immune system and commensal bacteria. Currently, major scientific emphasis has been aiming at the boundary area between mucosal immunology and symbiotic microbiology for an understanding of molecular and cellular mechanisms of recognizing commensal microflora as the part of self (or pseudo-self) antigen.

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Identification of Toll-like receptors (TLR) has led to elucidation of the mechanisms by which innate immunity senses invasion of pathogens and triggers host defense responses. In addition to TLRs, it has been revealed that cytoplasmic sensors such as NOD and RIG-I family of proteins are responsible for the recognition of pathogens in the cytoplasms. Innate immune responses, when in excess, have been shown to induce immune disorders such as chronic inflammatory bowel diseases. Therefore, activity of innate immune cells are finely regulated to prevent exaggerated inflammatory responses. As one of the mechanisms, IκBNS has been revealed to inhibit TLR-dependent induction of a subset of genes.

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The deployment of immune cells is essential in the gut since it has a wide surface area directly facing to the outer world. In general, there are certain rules for lymphocytes to be deployed into tissues. Nave T cells can immigrate into the secondary lymphoid organs, but cannot immigrate into non-lymphoid tissues. However, once they are activated in a secondary lymphoid organ and become effector/memory T cells, they can selectively immigrate into the tissue associated with the secondary lymphoid organ where they were activated. For example, T cells activated in the gut-associated lymphoid organs, Peyer's patches and mesenteric lymph nodes, express the gut-homing receptors, integrin α4β7 and chemokine receptor CCR9, and become capable of immigrating into the small intestinal tissues. We found that dendritic cells in gut-associated lymphoid organs imprint gut-homing specificity on T cells by producing retinoic acid from vitamin A and giving it to T cells during antigen presentation. Furthermore, retinoic acid also plays a critical role in imprinting B cells with gut-homing specificity and inducing their differentiation to IgA-producing cells.

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In this study, we investigated the effects of dietary nucleotides on the immune response balance between T helper cells type 1 (Th1) and type 2, and on the mucosal immune response in weanling mice. We have demonstrated that dietary nucleotides up-regulate the Th1 immune response and suppress the antigen-specific IgE antibody response in weanling mice. Thus, our results are suggesting that dietary nucleotides may be beneficial for the prevention of allergic diseases in early infancy. In addition, we showed that dietary nucleotides increased the proportion of a γδ T-cell receptor (TCR) -bearing intestinal intraepithelial lymphocyte (IEL) subset, IL-7 production by intestinal epithelial cells and the antigen-specific IgA response. Therefore, our study implies that dietary nucleotides may have an effect on the mucosal intranet in the intestinal mucosal immune system.

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