Once activated, the effector T cells that accumulate in the intestine behave much like their counterparts elsewhere in the body, producing cytokines and generating cytolytic activity as appropriate to the pathogen. What is different is that the aim of the protective immune response in the intestine is tailored to preserving the integrity and function of the epithelial barrier. This is achieved in a number of ways, depending on the nature of the pathogen. In virus infections, CD8 cytotoxic T cells among intraepithelial lymphocytes kill infected epithelial cells (see Fig 12.14), triggering their replacement by uninfected cells derived from the rapidly dividing stem cells in the crypts. A similar process can occur during other forms of protective immune responses, with cytokines from CD4 effector T cells directly stimulating epithelial cell division. This forces the replacement of infected cells and generates a moving target for organisms that are attempting to attach to the surface of the epithelium. An example of a cytokine of this kind is IL-13, produced by TH2 cells (and ILC2s) during parasitic infections. In addition to its ability to stimulate antimicrobial peptide production by Paneth cells, IL-22 produced by TH17 cells contributes to defense against extracellular bacteria and fungi by enhancing the tight junctions between epithelial cells that keep the barrier intact. Mucus is crucially important in protecting the epithelial barrier, and its production by goblet cells is enhanced by CD4 T-cell-derived cytokines such as IL-13 and IL-22, as well as by products of mast cells and other innate effector cells recruited by T cells. Finally, these mediators and others can enhance the peristaltic action of the intestine and its outward secretion of fluid, washing out pathogens within the lumen of the intestine. Together these processes aim to generate a hostile and unstable environment for the pathogen, reducing its ability to invade and damage the epithelial barrier.
12-18 The mucosal immune system must maintain tolerance to harmless foreign antigens.
Antigens within food and commensal bacteria normally do not induce an inflammatory immune response, despite the lack of central tolerance to them (Fig. 12.18). The mucosal immune system’s environment is inherently tolerogenic, and this is a barrier to the development of nonliving vaccines, which need to overcome local regulatory mechanisms. Food proteins are not digested completely in the intestine; significant amounts are absorbed into the body in an immunologically relevant form. The default response to oral administration of a protein antigen is the development of a phenomenon known as oral tolerance. This is a form of peripheral tolerance that renders the systemic and mucosal immune systems relatively unresponsive to the same antigen. It can be demonstrated experimentally in mice by feeding them a foreign protein such as ovalbumin (Fig. 12.19). When the animals are then challenged with the antigen by a nonmucosal route, such as injection into the skin, the immune response one would expect is blunted. This suppression of systemic immune responses is long lasting and is antigen specific: responses to other antigens are not affected. A similar suppression of subsequent immune responses is observed after the administration of proteins into the respiratory tract, giving rise to the concept of mucosal tolerance, as the usual response to such antigens is delivered via a mucosal surface. Systemic T-cell responses can also be inhibited by feeding humans protein antigens that they have not encountered previously.
Oral tolerance can impact all aspects of the peripheral immune response, including T-cell-dependent effector responses and IgE production. Effector T-cell responses in the mucosa are also downregulated in oral tolerance, although low levels of secretory IgA antibodies directed at food proteins can be found in healthy humans, but do not lead to inflammation.