IL-15: a central regulator of celiac disease immunopathology

Abstract

Interleukin-15 (IL-15) exerts many biological functions essential for the maintenance and function of multiple cell types. Although its expression is tightly regulated, IL-15 upregulation has been reported in many organ-specific autoimmune disorders. In celiac disease, an intestinal inflammatory disorder driven by gluten exposure, the upregulation of IL-15 expression in the intestinal mucosa has become a hallmark of the disease. Interestingly, because it is overexpressed both in the gut epithelium and in the lamina propria, IL-15 acts on distinct cell types and impacts distinct immune components and pathways to disrupt intestinal immune homeostasis. In this article, we review our current knowledge of the multifaceted roles of IL-15 with regard to the main immunological processes involved in the pathogenesis of celiac disease.

Keywords: IL-15; autoimmunity; celiac disease; cytotoxic T cells; loss of oral tolerance; tissue.

Fig. 1. Patients with active celiac disease have high IL-15 expression both in the intestinal lamina propria and epithelium, while patients on a gluten free diet only maintain high expression in the epithelium

Representative pictures of IL-15 immunohistochemistry staining are shown. Duodenal formalin fixed paraffin embedded sections were obtained from control non celiac subjects (control, left panel), untreated (active CD, middle panel), and treated celiac disease patients (GFD, right panel). Epithelial expression was assessed semi-quantitatively looking at staining intensity and localization (typically being stronger at the villous tip and then reducing its intensity going towards the crypts). The rate of IL-15 positive cells on the total number of infiltrating mononuclear cells in the lamina propria was assessed by two independent investigators in a double-blind set. Upregulation of IL-15 can be observed in both the small intestinal epithelium and lamina propria of active CD patients. Interestingly, celiac patients on a gluten-free diet (GFD) seem to retain only the epithelial but not the lamina propria IL-15 overexpression.

Fig. 2. Multifaceted roles of interleukin-15 (IL-15) in celiac disease pathogenesis

IL-15 impacts distinct cell types to mediate its pathogenic effects. (i) In the lamina propria, IL-15 endows mucosal dendritic cells with inflammatory properties in a c-Jun N-terminal kinase (JNK)-dependent manner, and subsequently with the ability to prevent the differentiation of regulatory T cells and to promote inflammatory Th1 cell responses leading to the loss of oral tolerance. (ii) IL-15 renders effector T cells resistant to the suppressive functions of regulatory T cells through a mechanism involving JNK and phosphatidylinositol 3 kinase (PI3K). (iii) IL-15 impacts on intraepithelial lymphocytes by inducing the expression of NKG2D. The synergy between IL-15 and NKG2D cytolytic signaling pathway promotes the binding of the NKG2D-DAP10 complex to distinct adaptor proteins including PI3K whose activation promotes the phosphorylation of the mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK), and JNK. This leads to cPLA₂ activation, which in turn critically regulates NKG2D-mediated degranulation and cytolysis, and induces the release of arachidonic acid, a precursor of the pro-inflammatory compounds called leukotrienes. (iv) In patients with refractory sprue, IL-15 leads to the expansion and survival of an abnormal subset of CD3⁻ intraepithelial lymphocytes by activating an anti-apoptotic cascade involving the phosphorylation of Jak3 and STAT5.

Fig. 3. Interactions between IL-15 and celiac disease susceptibility genes

(A). Network of known interactions between celiac disease (CD)-associated genes and IL-15. We used the STRING database to look for known functional interactions among CD susceptibility genes, as well as functional interactions between CD susceptibility genes and IL-15 (red). The figure only shows CD-associated genes that are directly or indirectly connected with IL-15. STRING database assembles information about both known and predicted protein-protein interactions on the basis of numerous sources, including experimental repositories, computational prediction method, and public text collections. We grouped genes based on the distance matrix obtained from the String global scores. We used the KMEANS algorithm setting the number of groups to three. Proteins pairs with a higher global core (i.e. stronger evidence that they interact together) are grouped together on the same cluster. The three clusters are represented by different colors (yellow, purple, and blue). IL-15 is directly connected with the ‘yellow cluster’. The thickness of the lines connecting the genes is proportional to String global scores supporting the evidence of an interaction. Solid and dashed lines represent intra- and inter-cluster connections, respectively. (B). KEGG pathway enrichment analysis for the CD-associated genes shown in panel A. The y-axis reports the fold enrichments observed for genes in a particular pathway (named in y-axis) using all human genes as our background expectation.

Fig. 4. Overlapping functions of IL-15, IL-21, and Type I interferon

Both IL-15 and IL-21 render effector CD4⁺ T cells resistant to the suppressive functions of regulatory T cells. Both IL-15 and Type I interferon endow dendritic cells with inflammatory properties and have been shown to mediate loss of oral tolerance and to promote Th1 immunity. All three cytokines have the ability to confer cytotoxic properties to CD8⁺ T cells.