Policing the intestinal epithelial barrier: Innate immune functions of intraepithelial lymphocytes

Abstract

Purpose of review: This review will explore the contribution of IELs to mucosal innate immunity and highlight the similarities in IEL functional responses to bacteria, viruses and protozoan parasite invasion.

Recent findings: IELs rapidly respond to microbial invasion by activating host defense responses, including the production of mucus and antimicrobial peptides to prevent microbes from reaching the epithelial surface. During active infection, IELs promote epithelial cytolysis, cytokine and chemokine production to limit pathogen invasion, replication and dissemination. Commensal-induced priming of IEL effector function or continuous surveillance of the epithelium may be important contributing factors to the rapidity of response.

Summary: Impaired microbial recognition, dysregulated innate immune signaling or microbial dysbiosis may limit the protective function of IELs and increase susceptibility to disease. Further understanding of the mechanisms regulating IEL surveillance and sentinel function may provide insight into the development of more effective targeted therapies designed to reinforce the mucosal barrier.

Keywords: intestine; intraepithelial lymphocytes; microbiota; mucosal immunity; pathogen; virus.

Figure 1. IELs and innate antibacterial immune responses

In the small intestine, pathogenic bacteria (red) induce upregulation of NKG2D ligands and release TCR-activating antigens, which signal via NKG2D and TCR to trigger the release of cytotoxic factors such as granzymes and Fas ligand (FasL). While TCR activation induces cytotoxicity in all IELs, NKG2D activation only promotes killing by natural IELs. Both pathogenic bacteria and invading commensals (green) promote γδ IEL epithelial surveillance, induce γδ IEL production of RegIIIγ and upregulate epithelial interleukin (IL)-23 production. In turn, IL-23 promotes γδ IEL production of IL-22 to further stimulate epithelial antimicrobial peptide (AMP) production. In the colon, HVEM/CD160 binding in response to pathogenic bacteria induces epithelial AMP production. Finally, DSS-induced injury enhances the translocation of commensal bacteria, resulting in γδ IEL production of AMPs and chemokines that serve to recruit myeloid cells to sites of damage.

Figure 2. Intestinal IELs promote antiviral innate immune responses

Induced (CD8αβ⁺) and natural (CD8αα⁺) IELs promote the cytolysis of virus-infected IECs through the production of perforin, granzyme B and IFNγ. This can be mediated in part through activation of TLR3, which promotes the expression of IEL NKG2D and its ligand Rae-1 leading to enhanced CD8αα cytotoxicity. Further, activated CD8αα⁺ IELs produce type I, II, III interferons (IFN) to enhance the epithelial antiviral response via induction of interferon-stimulated genes (ISG). This includes the production of chemokines CXCL10, CXCL11, CCL2 and CCL5, which can recruit both IELs and myeloid cells to facilitate viral clearance.