of a mucosal surface. sIgA can prevent such infections by blocking colonization. Thus, while the cell-mediated or humoral antibody responses may cause collateral damage to tissues in the area where infection is occurring, the sIgA-mediated defense is usually innocuous to the host because it occurs in the mucus layer.
As we mentioned in chapter 2, skin and mucosal surfaces all have attendant mucosa-associated lymphoid tissues (MALT) located just below the epithelial layer in the lamina propria. The mucosal surface of the small intestine is underlain with the GALT, while the lungs have BALT, the upper respiratory tract has NALT, and the vaginal tract has vaginal-associated lymphoid tissue (VALT). Skin also has a similar system (called SALT).
The intestinal cells that comprise the GALT are visible as a collection of follicles, called Peyer’s patches, which are most highly concentrated in the ileum and rectum of the intestine. Similar mucosal lymphoid tissues are found in the respiratory and vaginal tracts, although they are not as pronounced. The cells that form the Peyer’s patches are illustrated in Figure 4-12. M (microfold) cells take up antigens from the lumen of the intestinal tract and pass them to closely associated GALT macrophages, which act as the APCs of the GALT. M cells have never been successfully cultivated in vitro, so little is known about the activities of M cells. The mechanism by which GALT macrophages process antigens and elicit production of cytotoxic T cells or antibodies is the same as that described in earlier sections, except that the macrophages, B cells, and T cells of the GALT reside specifically in the lamina propria of mucosal surfaces. Two additional types of T cells, Th17 and Tregs, appear to be important for IgA production in the intestine, both of which appear to help modulate the B cells.
Figure 4-12. Cells of the GALT that confer mucosal immunity. M cells and their associated macrophages and lymphoid cells (T and B cells) are sometimes called follicles. Collections of such follicles in the gut are called Peyer’s patches. M cells sample the contents of the gut lumen and transfer the antigens to closely associated resident macrophages, which in turn ingest the bacteria and present antigens to the underlying T cells that then stimulate nearby B cells to produce IgA. The IgA binds to receptors on the basal surface of the mucosal epithelial cell and is transcytosed across the cell and secreted into the lumen of the gut as sIgA.
When the GALT is stimulated, one outcome is production of IgA (see Figure 4-12). Dimeric IgA is produced by plasma cells in the lamina propria at mucosal sites. The secretory piece is acquired when IgA dimer is transported through the mucosal epithelial cell into mucosal secretions covering various mucosal surfaces. IgA dimer binds to the poly-Ig receptor on the basal surface of mucosal cells and is then taken up by endocytosis and transported in vesicles, through a process called transcytosis, to the apical surface, where it is released into the lumen of the gut. Release involves proteolytic cleavage of the poly-Ig receptor, where the secretory piece comes from the portion of the receptor that remains attached to the IgA, making it sIgA. sIgA can trap microbes in mucus because the Fc portion of sIgA binds to glycoprotein constituents of the mucin and the Fab portion binds to antigens on the microbes in the gut. By trapping the microbes in the mucus layer, the sIgA-antigen-mucin complex essentially forms a protective barrier that blocks the microbes and their toxic products from gaining access to the epithelial cell layer. Mucus laden with sIgA-coated microbes is then sloughed off and excreted from the body.
The mucosal and skin tissues that have contact with the external environment are also constantly patrolled by DCs (APCs), which engulf and kill the invading microbes and process the antigens for presentation to the adaptive immune system. Once activated, DCs migrate to the lymph nodes, where they present the antigens to Th cells and stimulate adaptive immunity. The Langerhans cells of the epidermis are the DCs of SALT.
As part of the mucosal immune system, some T cells and B cells stimulated by antigen processing at the GALT can migrate to other mucosal sites and vice versa. Thus, stimulation at one of the MALT sites can transfer to other sites, resulting in general mucosal immunity. The first evidence for this feature of the mucosal immune system came from elegant experiments performed by Husband and Gowans in the late 1970s. These researchers excised a segment of the small intestine from a rat, preserving its vascular and lymphatic supplies, and reconnected the ends of the intestinal segment to the skin surface of the animal, forming a so-called Thiry-Vella loop (Figure 4-13). They then introduced an antigen, in this case cholera toxin (CT), into the loop and found that sIgA was secreted in not only the immunized loop segment, but also in a second such loop (when made) and in the main intestine. Their results demonstrated that introduction of an immunogen at one site could confer mucosal immunity at a remote site. This characteristic of the MALT system is what makes oral vaccines feasible. Initially, oral vaccines stimulate the GALT, but sIgA against vaccine antigens is later detectable in other MALT sites. Thus, an oral vaccine can also be used to elicit immunity to respiratory and, presumably, urogenital pathogens.
Figure 4-13. Classic experiment by Husband and Gowans demonstrating mucosal immunity at remote sites. The experimental setup involved isolating Thiry-Vella loops of the small intestine of rats and connecting them to the skin, preserving the associated vascular and lymphatic systems attached to the loops. The IgA immune response to administering immunogen (cholera toxin) to the main intestine through the oral route or through the skin opening of the loop could then be observed. Results showed that local immunization through the isolated loops that contained Peyer’s patches generated Th cells and B cells that circulated through the lymph and blood to populate other mucosal sites. Based on Husband AJ, Gowans JL. 1978. J Exp Med 148:1146–1160.
Currently, efforts are being made to develop vaccines administered by inhalation, so that stimulation of the nasal MALT (NALT) would produce an sIgA response at other MALT sites. These vaccines would have the advantage of not having to pass through the stomach. Developing vaccines that target the GALT means developing vaccines capable of surviving the low-pH/protease-rich stomach environment, a barrier that has proven problematic in many cases. Administering vaccines by rectal or vaginal suppositories is theoretically possible, but this strategy has not been actively pursued to date. On the other hand, the SALT is gaining in attraction as a target for vaccine development (more on vaccines in chapter 17).
Activation of the GALT can also lead to production of cytotoxic T cells. These cells probably remain on the basal side of the mucosa, although it is possible that during an infection some of them migrate to the apical surface, especially in areas where damage to the mucosa has occurred. GALT cytotoxic T cells are important for protection against viral infections of the GI tract and some bacterial infections in which the bacteria multiply inside mucosal cells.
One of the many mysteries swirling around the intestinal immune system is the role of a particular type of mucosal cell called γδ T cells. The majority of γδ T cells are CD8+ T cells and would thus be grouped with CTLs. However, whereas CTLs have TCRs composed of αβ chains (Figure 4-8), the intestinal epithelial lymphocytes (IELs) have T-cell receptors composed of related but somewhat different γδ chains. These γδ T cells account for less than 4% of circulating CD8+ T cells, but they account for as much as 10 to 15% of the mucosal T cells found in the GI tract. In some regions, such as the colon, the levels may be as high as 40%.
Unlike αβ T cells, γδ T cells seem to recognize only a limited number of cell-surface antigens. Also, γδ T cells seem to bypass antigen presentation by MHCI and MHCII on the surfaces of macrophages and DCs and directly recognize
