Lamina propria CD4 T cells secrete large amounts of cytokines such as interferon (IFN)-γ, IL-17, and IL-22, even in the absence of overt inflammation. This likely reflects the constant state of immune recognition of the microbiota and other environmental antigens that takes place in the intestine, and their importance is underlined by the frequent opportunistic infections of the intestine that occur in individuals lacking CD4 T cells, such as those with HIV infection (see Section 13-24). Effector TH17 cells are prominent in the intestinal mucosa, and their products are important components of local immune defense. IL-17 is needed for full expression of the poly-immunoglobulin receptor involved in secretion of IgA into the lumen, while IL-22 stimulates intestinal epithelial cells to produce antimicrobial peptides that help maintain epithelial barrier integrity. Effector CD8 T cells are also present in the normal lamina propria and are capable of both cytokine production and cytotoxic activity when a protective immune response to a pathogen is required.
In any other situation, the presence of such large numbers of differentiated effector T cells would suggest the presence of a pathogen and likely would lead to inflammation. The fact that it does not in the healthy lamina propria is because the generation of TH1, TH17, and cytotoxic T cells is balanced by the presence of substantial numbers of IL-10-producing regulatory T cells. In the small intestine, these are mostly FoxP3-negative, whereas in the colon, FoxP3positive T cells dominate. Many of the inducible T cells recognize antigens derived from organisms within the microbiota.
The healthy lamina propria also contains many innate lymphoid cells (ILCs) (see Sections 1-19 and 9-20). The ILC3 subset is prominent in both human and mouse intestinal mucosa. Mature ILC3s produce IL-17 and IL-22, and some express the NK-cell receptors NKp44 and NKp46. Their development is controlled by the aryl hydrocarbon receptor and the transcription factor RORγT (see Section 9-21). ILC3s are present in secondary lymphoid organs in the intestine and are important for their lymphoid tissue development there. In response to IL-23 secreted by local dendritic cells, ILC3s produce IL-22, which stimulates the epithelium to generate antimicrobial peptides that promote local defense against bacterial and fungal pathogens in the intestine. During the course of inflammatory diseases, ILC3s can acquire the ability to produce IFN-γ in response to IL-12, and combined with their production of IL-17, this endows them with significant pathological properties. IL-5 and IL-13 produced by ILC2s form an important layer of T-cell-independent responses to helminth parasites in the intestine, and an equivalent population is involved in allergic reactions in the respiratory tract.
CD1-restricted iNKT cells (see Section 6-18) and mucosal invariant T (MAIT) cells (see Section 6-19) are also present in the lamina propria, and account for 2–3% of lamina propria T cells in human small intestine. MAIT cells express an invariant TCRα chain paired with a limited range of TCRβ chain and recognize metabolites of vitamin B derived mainly from the riboflavin metabolism pathway in microbes presented by MR1.
12-14 The intestinal epithelium is a unique compartment of the immune system.