Sentinels at the Frontline: the Role of Intraepithelial Lymphocytes in Inflammatory Bowel Disease

Abstract

Purpose of review Intestinal mucosal immunity is tightly regulated to ensure effective host defense against invasive microorganisms while limiting the potential for aberrant damage. In inflammatory bowel disease (IBD), an imbalance between effector and regulatory T cell populations results in an uncontrolled inflammatory response to commensal bacteria. Intraepithelial lymphocytes (IEL) are perfectly positioned within the intestinal epithelium to provide the first line of mucosal defense against luminal microbes or rapidly respond to epithelial injury. This review will highlight how IELs promote protective intestinal immunity and discuss the evidence indicating that altered IEL responses contribute to the pathogenesis of IBD. Recent findings Although the role of IELs in mucosal homeostasis has been largely underappreciated, many of the same factors that contribute to the dysregulation of host defense in IBD also adversely affect IELs. For example, IL-23 and the endoplasmic reticulum stress response can enhance IEL lytic activity toward enterocytes. Microbial dysbiosis or defective microbial recognition results in the loss of regulatory IELs, further amplifying these pro-inflammatory effects. Migration of T cells into or within the intraepithelial compartment has a profound effect on their differentiation or effector function demonstrating that IELs are exquisitely sensitive to changes in the local intestinal microenvironment. Summary Enhanced mechanistic insight into the regulation of IEL survival, differentiation and effector function may provide useful tools to modulate IEL surveillance or enhance IEL regulatory function. Elucidation of these processes may result in the development of novel therapeutics to reduce intestinal inflammation and reinforce the mucosal barrier in IBD.

Development, Homeostasis, and Functions of Intestinal Intraepithelial Lymphocytes

“…These cells are also enriched in immunomodulatory factors, including TGF-β3, lymphocyte activating 3 (LAG-3, which is involved in immunosuppression by regulatory T cells), and fibrinogen-like protein 2 (Fg1–2, which suppresses DC maturation) (116). Consistent with this transcriptional profile, CD8αα + TCRαβ + iIEL protect mice against colitis induced following adoptive transfer of naïve CD4 + T cells into immunodeficient animals, in a manner that requires IL-10 production (Table 1) (117, 118).…”

“…In patients with inflammatory bowel disease, disease severity correlates with increased numbers of TCRγδ + cells in the intestinal mucosa (128, 129). In several models of colitis, TCRγδ + T cells promote inflammation (118, 130–133). However, in later stages of colitis, these cells can protect the epithelium against inflammation-induced damage (118, 134–136).…”

“…In several models of colitis, TCRγδ + T cells promote inflammation (118, 130–133). However, in later stages of colitis, these cells can protect the epithelium against inflammation-induced damage (118, 134–136). Consistent with this role in strengthening the epithelial barrier, TCRγδ + iIELs have been implicated in promoting the induction and maintenance of oral tolerance in mice (137, 138).…”

CD4CD8αα IELs: They Have Something to Say

“…IELs are perfectly positioned within the intestinal epithelium to provide the first line of mucosal defense against luminal microbes or rapidly respond to epithelial injury. Their special position predestined them to participate in the early immune reaction (61). Ooi et al (62) believed that the cause of IBD is inappropriate T cell responses to the normal bacterial flora in the gut.…”

Policing the Intestinal Epithelial Barrier: Innate Immune Functions of Intraepithelial Lymphocytes

“…IEL biology has been well-characterized in the context of celiac disease;[4] however, relatively little is known about the role of IELs in inflammatory bowel disease (IBD), where epithelial barrier dysfunction is thought to precede disease development. [109–111] This is of particular interest since microbial dysbiosis, diet and defects in microbial recognition are contributing factors to the pathogenesis of IBD. [112] Recent reports have begun to explore how IBD-associated defects in innate immunity affect IEL function,[35] yet this is still a largely underappreciated area of investigation that has been recently reviewed elsewhere.…”