T cells play important roles in protection against microbial pathogens in the gastrointestinal system and in regulating responses to food and commensal antigens. Furthermore, T cells contribute to inflammatory diseases in the gastrointestinal tract. As in other parts of the body, T-cell immunity in the gut involves different subsets of T cells and is influenced in various ways by antigen-presenting DCs, which also belong to different subsets. In this section, we will discuss important features of T-cell and DC functions in the intestines.
T cells are found within the gut epithelial layer, scattered throughout the lamina propria and submucosa, and around and within follicles in Peyer’s patches and other GALT structures. In humans, the intraepithelial T cells are mostly conventional CD8+ and CD4+ cells with αβ TCRs, with four to six times more CD8+ than CD4+ T cells. From 1% to 20% of the intraepithelial T cells express the γδ TCR, with higher percent ages in the colon than small intestine; overall, the percentages of γδ cells among intestinal T cells are higher than in other tissues. Several functional subsets of human intraepithelial T cells have been identified by single-cell analyses, including CTLs, Th17, Th2, and Treg. Most of these cells have a tissue-resident memory phenotype. Both the αβ and the γδ TCR-expressing intraepithelial lymphocytes have a limited diversity of antigen receptors, and thus a limited range of specificities compared to most T cells. This restricted repertoire may have evolved to recognize microbes that are commonly encountered at the epithelial sur face. Studies in mice indicate that oligoclonal intraepithelial T cells are already present at birth, suggesting that the repertoire is not changed by exposure to microbes, although total numbers and differentiation into effector and tissue-resident memory cells in adults may reflect antigen experience. Lamina propria T cells are mostly CD4+, and most have the phenotype of previously activated effector or memory T cells (see Chapter 9). Many of the memory T cells are noncirculating tissue-resident memory cells. Recall that these lamina propria effector and memory T cells are generated from naive precursors in the GALT and mesenteric lymph nodes, enter the circulation, and preferentially home back into the lamina propria (see Fig. 1). T cells within Peyer’s patches and in other follicles adjacent to the intestinal epithelium are mostly CD4+ helper T cells, including Tfh cells and regulatory T cells.
Fig1. Homing properties of intestinal lymphocytes. The gut-homing properties of effector lymphocytes are imprinted in the lymphoid tissues, where they have undergone differentiation from naive precursors. Dendritic cells in gut-associated lymphoid tissues (GALT), including Peyer’s patches and mesenteric lymph nodes, are induced by cytokines such as thymic stromal lymphopoietin (TSLP) and other factors to express retinaldehyde dehydrogenase (RALDH), which converts dietary vitamin A into retinoic acid. When naive B or T cells are activated by antigen in GALT, they are exposed to retinoic acid produced by the dendritic cells, and this induces the expression of the chemokine receptor CCR9 and the integrin α4 β7 on the differentiated plasmablasts and effector T cells. The effector lymphocytes enter the circulation and home back into the gut lamina propria because the chemokine CCL25 (the ligand for CCR9) and the mucosal addressin cell adhesion molecule 1 (MAdCAM -1) (the ligand for α4 β7 ) are displayed on lamina propria venular endothelial cells.
DCs and macrophages are abundant in the gastrointestinal immune system and can participate in stimulating protective effector T-cell responses or inducing regulatory T-cell responses that suppress immunity to ingested antigens and commensal organisms. DCs in the lamina propria take up and process protein antigens from microbes that are in the lumen or have breached the epithelial barrier and transport these antigens via lymphatics to mesenteric lymph nodes (Fig. 2). Within the mesenteric lymph nodes, DCs present processed protein antigens to naive T cells and induce the differentiation of these T cells into Th1, Th2, or Th17 effector cells or into peripheral FOXP3+ Tregs. Some macrophages in the terminal ileum of the gut project dendrites between epithelial cells and sample luminal contents (see Fig.2). These specialized antigen-sampling cells, identifiable by expression of the chemokine receptor CX3CR, maintain epithelial barrier integrity despite protruding their dendrites between the epithelial cells, by producing the same junctional proteins that the epithelial cells express. These DCs promote protective adaptive immune responses to pathogens in the lumen by passing the sampled antigens to more mobile lamina propria DCs, which then migrate to mesenteric lymph nodes and activate T-cell responses to those antigens. Another pathway for delivery of low-molecular-weight luminal antigens to lamina propria DCs is through passages that form within goblet cells after they have secreted mucus.
Fig2. Antigen sampling by intestinal macrophages and dendritic cells (DCs). Macrophages and DCs are present in the intestinal mucosa and sample antigens for presentation to T cells in gut-associated lymphoid tissues and mesenteric lymph nodes. (A) Some macrophages extend dendritic processes between intestinal epithelial cells into the lumen to sample antigens and then pass the antigens to mobile lamina propria DCs, which migrate into mucosa-associated lymphoid tissue (MALT) and present the antigens to naive T cells. Macrophages may also sample luminal antigens in this manner. (B) The lamina propria DCs also sample antigens that are derived from luminal contents and have gotten through the epithelial barrier and present the antigens to naive T cells in MALT.
In the gastrointestinal tract, different subsets of effector CD4+ T cells are induced by and protect against different microbial species (Fig. 3). we introduced the concept that helper T-cell subsets that secrete different cytokines are specialized for protection against different types of microbes. This fundamental concept is highly relevant to the mucosal immune system. Th1, Th2, and Th17 cells are found in the epithelia and lamina propria of the intestine, and the com mensal bacterial microflora of the gut lumen exerts profound influences on T-cell phenotypes, even during homeostasis.
• Th17 cells. Studies in mice have shown that certain classes of bacteria, or in some cases individual species of bacteria, can shift the dominant pattern of T-cell cytokine production. For example, the lamina propria of the small bowel in healthy mice is particularly rich in IL-17-producing cells, whereas the colon is not. The abundance of the Th17 cells depends on colonization of the gut with a certain phylum of bacteria (segmented filamentous bacteria) in the postnatal period. These and other bacteria stimulate intestinal epithelial cell production of factors such as serum amyloid A that enhance the release of IL-1, IL-6, and TGF-β by DCs, thereby promoting Th17 differentiation. Substances derived from food or intestinal microbes activate the transcription factor aryl hydrocarbon receptor in Th17 cells, which is required for secretion of IL-22. The steady-state presence of Th17 cells is required for protection against pathogenic species of bacteria (e.g., Citrobacter rodentium). Th17 cells appear to play a special role in maintaining mucosal epithelial barrier function because of the actions of the two signature cytokines they produce, IL-17 and IL-22, which, as discussed earlier, are also produced by the group 3 subset of ILCs in the gut. The receptors for both these cytokines are expressed on intestinal epithelial cells, and both induce the expression of proteins important for barrier function, such as mucins and β-defensins, which protect the epithelial cells against microbe-induced injury.
• Th2 cells. Intestinal helminthic infections induce strong Th2 responses, which are effective in eliminating the worms because the Th2 cytokines IL-4 and IL-13 cooperate in enhancing fluid and mucus secretions and inducing smooth muscle contraction and bowel motility.
• Th1 cells are relatively sparse in healthy lamina propria compared to Th17 or Th2 cells, but their numbers increase in the setting of IBD, and they may contribute to the pathogenesis of this disorder.
Fig3. Effector and regulatory T cells in the intestinal mucosa. Th17 effector T cells and regulatory T cells are abundant in the intestinal mucosa. Bacterial antigen–specific Th17 cells differentiate from naive CD4+ T cells in gut-associated lymphoid tissues (not shown) in response to antigens presented by dendritic cells (DCs) and cytokines they secrete, including interleukin-6 (IL-6) and IL-23. Differentiation of bacterial anti gen–specific regulatory T cells (Tregs) is promoted by transforming growth factor-β (TGF-β) and retinoic acid produced by intestinal epithelial cells. Thymic Tregs that migrate to the intestine expand in number under the influence of bacterial metabolites. Regulatory T cells require antigen presentation by DCs (not shown); the nature of these antigens is unknown.
