Macrophages are important for maintaining a healthy intestine. They are positioned immediately under the epithelium and are highly phagocytic, and thus ideally suited to ingest and degrade any microbes that penetrate across the epithelial barrier. They can also clear away dying epithelial cells, which are found in large numbers in the intestine, an inevitable consequence of such a rapidly dividing tissue. However, unlike macrophages in other parts of the body, intestinal macrophages do not produce significant quantities of inflammatory cytokines or reactive oxygen or nitrogen species in response to phagocytosis or exposure to stimuli such as bacteria or TLR ligands. This is because they produce large amounts of IL-10 constitutively, allowing them to limit inflammation while acting as powerful scavengers. Macrophage-derived IL-10 also contributes to maintaining antigen-specific tolerance in the mucosa, as it is needed to sustain the survival and secondary expansion of FoxP3+ Treg cells that have migrated back to the intestine after being primed by tolerogenic dendritic cells in the lymph node. Indeed, they have features of both these populations, and their functions are specifically adapted to the conditions of their local environment. Thus macrophages and dendritic cells play distinct but complementary roles in the steady-state intestine. Migratory dendritic cells carry out the initial priming and shaping of T-cell responses in secondary lymphoid organs, and sessile macrophages scavenge cellular debris and microbes and may tune the activity of already primed T cells in the mucosa itself.
12-9 Antigen-presenting cells in the intestinal mucosa acquire antigen by a variety of routes.
The total surface area provided by M cells in the epithelium of Peyer’s patches for antigen to the intestinal immune system is limited, and the lamina propria itself is covered by an intact epithelium. Various additional mechanisms have been proposed to explain how antigen crosses the epithelium to gain access to macrophages and dendritic cells (see Fig. 12.10). Soluble antigens such as food proteins might be transported across epithelial cells or between gaps formed in the epithelium where dying cells are being shed. Alternatively, M cells may reside in the surface epithelium of the mucosa outside Peyer’s patches. Some intestinal bacteria, such as enteropathogenic and enterohemolytic strains of E. coli, have specialized means of attaching to and invading epithelial cells, allowing them to enter the underlying lamina propria directly. Antigen from the lumen can be delivered to lamina propria dendritic cells by uptake of antibody-coated antigens by epithelial cells expressing the neonatal Fc receptor (FcRn). Antigen derived from apoptotic epithelial cells may be processed by cross-presenting dendritic cells (see Section 6-5) for induction of immune responses against enteric viruses, such as rotaviruses, which cause diarrheal disease because of their specialized ability to infect enterocytes (see Fig. 12.10).
Macrophages in the lamina propria may also participate in local antigen uptake by sending transepithelial dendrites that extend between epithelial cells and reach the lumen to sample bacteria (see Fig. 12.10). Lamina propria macrophages have also been reported to take up soluble antigen from the lumen, passing it on to dendritic cells for subsequent presentation to T cells. Some experiments also suggest that dendritic cells or macrophages might make their way into the lumen to acquire antigens such as bacteria, before returning with them to the lamina propria.
12-10 Secretory IgA is the class of antibody associated with the mucosal immune system.