Intestinal Intraepithelial Lymphocytes: Sentinels of the Mucosal Barrier

The intestinal epithelium contains large numbers of IELs that promote its barrier function. Most IELs are TCR+, entering the epithelium after antigen encounter in the periphery (induced TCR+ IELs) or immediately after development (natural TCR+ IELs). Recent studies have identified subsets of TCR− IELs that resemble innate lymphoid cells, and cells expressing CD3 chains intracellularly, including a subtype that expresses CD8αα (iCD8α cells). IELs have diverse developmental requirements: induced TCR+ IELs develop similarly to peripheral T cells, natural TCRαβ+ IELs undergo thymic agonist selection, many TCRγδ+ IELs develop extrathymically, and TCR− IELs develop similarly to subsets of peripheral innate lymphocytes. Interactions between IELs and IECs influence IEL homeostasis and function. IEL subsets communicate with each other and with immune cells outside the epithelium. Intestinal intraepithelial lymphocytes (IELs) are a large and diverse population of lymphoid cells that reside between the intestinal epithelial cells (IECs) that form the intestinal mucosal barrier. Although IEL biology has traditionally focused on T cells, recent studies have identified several subsets of T cell receptor (TCR)-negative IELs with intriguing properties. New insight into the development, homeostasis, and functions of distinct IEL subsets has recently been provided. Additional studies have revealed intricate interactions between different IEL subsets, reciprocal interactions between IELs and IECs, and communication of IELs with immune cells that reside outside the intestinal epithelium. We review here sentinel functions of IELs in the maintenance of the mucosal barrier integrity, as well as how dysregulated IEL responses can contribute to pathology. Intestinal intraepithelial lymphocytes (IELs) are a large and diverse population of lymphoid cells that reside between the intestinal epithelial cells (IECs) that form the intestinal mucosal barrier. Although IEL biology has traditionally focused on T cells, recent studies have identified several subsets of T cell receptor (TCR)-negative IELs with intriguing properties. New insight into the development, homeostasis, and functions of distinct IEL subsets has recently been provided. Additional studies have revealed intricate interactions between different IEL subsets, reciprocal interactions between IELs and IECs, and communication of IELs with immune cells that reside outside the intestinal epithelium. We review here sentinel functions of IELs in the maintenance of the mucosal barrier integrity, as well as how dysregulated IEL responses can contribute to pathology. an inflammatory disorder of the gut due to an immune reaction against gluten in food products in genetically predisposed individuals. a type of inflammatory bowel disease that may affect any part of the gastrointestinal tract; caused by a combination of environmental, microbial, and immune factors in genetically susceptible individuals. small aggregates of lymphoid cells found in the intestinal lamina propria. the forkhead box P3 transcription factor functions as a master regulator for the development and function of regulatory T cells. a member of the inhibitor of DNA binding (ID) family of transcription factors that is crucially important for the development of all subsets of innate lymphoid cells. a family of innate lymphocytes that require the transcription factors Id2 and Nfil3 for their development and exhibit functions analogous to distinct effector T cell subsets. a layer of connective tissue beneath the epithelium of mucosal membranes. a small, non-polymorphic protein that binds non-covalently with MHC class I heavy chains. It is crucially important for surface expression of all classical MHC class I molecules and many non-classical MHC class I molecules (e.g., CD1d, Qa-2, and TL). the myeloid differentiation gene 88 product is an adaptor protein crucial for signaling through most Toll-like receptors. nuclear factor, interleukin-3 regulated (also called E4BP4) is a bZIP transcription factor required for the development of all subsets of innate lymphoid cells. glycoproteins related to the classical MHC molecules that exhibit limited polymorphism, expression patterns, and presented antigens. a receptor of the conserved Notch signaling pathway that is crucial for T cell lineage commitment. these mice exhibit a spontaneous mutation in the Foxn1 transcription factor that causes abnormal hair growth and defective development of the thymic epithelium, resulting in the absence of T cells. small lymphoid follicles throughout the ileum of the small intestine. an inhibitory surface receptor expressed by chronically activated or regulatory T cells that plays a crucial role in downregulating immune responses. the RAG1 and RAG2 products are crucial for the rearrangement of B and T cell receptor genes. a metabolite of vitamin A that binds with its nuclear receptor in lymphocytes to promote mucosal tolerance. a transcription factor that is crucial for the differentiation of T helper 17 cells. the Runt-related transcription factor-3 acts as a key regulator for commitment of immature T cells to the CD8 lineage. a T-box transcription factor encoded by the Tbx21 gene and selectively expressed by T helper 1 cells to control expression of the Ifng gene. the T helper-inducing POZ/Krüppel factor acts as a key regulator for commitment of immature T cells to the CD4 lineage. closely associated areas between cells whose membranes join together to form a barrier.