mean that it presents a formidable barrier to invasion, by trapping microbes and other particles. At the same time, it acts as a scaffolding to retain IgA antibodies and antimicrobial peptides that have been secreted into the lumen across the epithelium. Mucus is also slippery in nature, meaning that trapped materials can then be expelled easily by normal peristaltic movements. In the intestine, there are two layers of mucus, an outer loose layer and a much denser inner layer, found mostly in the large intestine. Although bacteria can penetrate the loose layer of mucus, they are normally kept away from the surface of the epithelial cells by the inner dense layer, and defects in this structure compromise antimicrobial defense.
As we have discussed, the intestinal mucosa is also rich in cells of the innate immune system that can respond rapidly to infection. These include macrophages, eosinophils, mast cells, ILCs, MAIT cells, NKT cells, and γ:δ T cells.
12-16 Pathogens induce adaptive immune responses when innate defenses have been breached.
If pathogenic bacteria and viruses gain access to the subepithelial space, they may interact with TLRs on inflammatory cells in the underlying tissue. Together with the cascade of inflammatory mediators released by epithelial cells, this dramatically alters the environment of the mucosa and changes the behavior of local antigen-presenting cells such as dendritic cells. As described in Section 9-8, activated dendritic cells will express high levels of co-stimulatory molecules and cytokines such as IL-1, IL-6, IL-12, and IL-23, and promote development of effector T cells. Dendritic cells activated in Peyer’s patches migrate to the T-cell-dependent areas of the patch, whereas dendritic cells that encounter antigen in the lamina propria migrate to the mesenteric lymph node under control of CCR7. The effector T cells activated in these ways acquire gut-homing molecules such as α4:β7 and CCR9 due to the presence of retinoic acid, ensuring that they return to the gut wall to encounter the invading organisms. Similarly, IgA-producing B lymphocytes are generated in Peyer’s patches and mesenteric lymph nodes, generating plasma cells that accumulate in the lamina propria. IgA secretion into the lumen is enhanced in response to infection because pIgR expression is enhanced by TLR ligands and pro-inflammatory cytokines. In some infections, IgG antibodies can now be found in intestinal secretions, but these are derived from serum and require invading organisms to reach systemic immune tissues.
The activated myeloid cells found in the inflamed mucosa also contribute to sustaining the functions of effector T and B cells after their arrival in the mucosa. IL-1 and IL-6 produced by recently arrived monocytes are important for maintaining the survival and function of local TH17 cells. Pro-inflammatory myeloid cells also produce mediators such as IL-6, TNF-α, and nitric oxide that help drive IgA switching and secondary expansion of mucosal B cells.
12-17 Effector T-cell responses in the intestine protect the function of the epithelium.