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Intraepithelial T cells: Specialized T cells at epithelial surfaces
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Although some conventional CD8αβ+ recent thymic emigrants have gut-homing receptors, in general, conventional thymically selected precursor cells and naive CD8 or CD4 T cells are not detected within the intestinal epithelium. However, organized lymphoid tissue, such as the PP and the MLN, form the main priming sites for peripheral naive T cells that acquire gut-homing capacity upon activation with their cognate antigens. In that aspect, specialized epithelial cells or M cells (discussed in Chapter 15), resident CX3CR1+ macrophages, and migratory CD103+ dendritic cells (DC) (discussed in Chapter 12) all have the unique capacity to directly or indirectly sample the antigen content of the gut lumen, allowing for constant reporting on the condition of the intestinal compartment. Upon priming in these mucosal sites, activated naive T cells are induced to express gut-homing receptors that drive migration to the intestine (Figure 6.5). The ability of the mucosal DC to confer these properties is mediated at least in part by the release of a diet-derived factor, the vitamin-A metabolite retinoic acid (RA), which preferentially promotes migration to the small intestine, through induction of CCR9. The RA-mediated homing process greatly promotes migration to the intestine, but it is not absolutely required, and TCRαβ T cells activated in the periphery can also migrate to the gut, although under conditions of an intestinal challenge gut-specific homing may be significantly enhanced through RA-mediated imprinting.
Controlling in and out – the future of interfering with immune cell trafficking in inflammatory bowel disease
Published in Expert Review of Clinical Immunology, 2023
Sebastian Zundler, Lisa Lou Schulze, Markus F. Neurath
Leukocytes that are destined to enter the intestine to encounter and combat potential pathogens and to fulfill their effector functions express certain gut-specific homing molecules, e.g. α4β7 integrin, C–C chemokine receptor type 9 (CCR9), or G protein-coupled receptor 15 (GPR15) [13]. These molecules enable them to specifically home into their target tissue. The process of such cell homing into the tissue is a tightly regulated multistep process, also termed leukocyte extravasation cascade, and can be divided into three main steps: rolling, adhesion, and transmigration [13,14].
PF-00547659 for the treatment of Crohn’s disease and ulcerative colitis
Published in Expert Opinion on Investigational Drugs, 2018
Mariangela Allocca, Daniela Gilardi, Gionata Fiorino, Federica Furfaro, Marjorie Argollo, Laurent Peyrin-Biroulet, Silvio Danese
Gut-specific homing, the mechanism by which activated leukocytes are targeted to Peyer’s patches, mesenteric lymph nodes, and mucosal sites of the gastrointestinal tract, is mainly mediated by the expression of MAdCAM-1 on endothelial cells [13]. TNF-α increases endothelial MAdCAM-1 expression, and it has been shown a two-to-threefold increase in MAdCAM-1 expression at sites of inflammation in patients with IBD [14].
Dynamics and clinical significance of intestinal intraepithelial lymphocytes
Published in Immunological Medicine, 2019
IELs in the small intestine are distributed throughout the epithelium that overlies small intestinal villi. Even under homeostatic conditions, IELs actively migrate almost in the space between the epithelial layer and the basement membrane and occasionally showed transient movements in close association with epithelial cells (Figure 1) [17–19]. IEL-homing to the intestine and retention in the intestinal mucosa are critically dependent on the expression of a variety of gut-specific homing molecules (Table 1). β7 integrin and CC-chemokine receptor 9 (CCR9) have been well-known to be gut-homing receptors under homeostatic conditions [20]. In particular, the number of IELs was significantly reduced in all small intestinal segments of β7 integrin-deficient mice when compared to controls. In addition, the gut-associated lymphoid tissues (GALTs), comprising Peyer's patches and lamina propria lymphocytes of the intestine, appeared hypoplastic in β7 integrin-deficient mice [21,22]. In CCR9-deficient mice, the total numbers of IELs was diminished 2-fold in compared with wild-type mice and these decrease in IELs was mainly due to the presence of low numbers of TCRγδ+ IELs [23]. Natural IEL precursors such as CD8αα+ IELs have been reported to develop and express gut-homing receptors in the thymus [24–26]. On the other hand, induced IELs such as CD8αβ+ IELs and naive T cells generally do not express mucosal homing receptors are normally not detected within the intestinal epithelium. However, in these populations, gut-homing molecules β7 integrin and CCR9 are induced in GALTs, such as Peyer’s patches [27] and in mesenteric lymph nodes [28]. In these processes, the vitamin A metabolite, retinoic acid, is a key inducer of gut-homing-related molecules, upregulating β7 integrin and CCR9 [29]. Regarding the ligands for β7 integrin and CCR9, E-cadherin and CC-chemokine ligand 25 (CCL25) expressed in small intestinal epithelial cells, respectively [25]. The number of IEL in CCL25-deficient mice was reduced to the similar extent in CCR9-deficient mice [30].