Epithelium derived interleukin 15 regulates intraepithelial lymphocyte Th1 cytokine production, cytotoxicity, and survival in coeliac disease

Abstract

Background and aims: Epithelium derived interleukin (IL)-15 signalling via IL-15Ra is critical for the development, activation, and survival of intraepithelial lymphocytes (IEL). We aimed to better understand the IL-15 driven effects on IEL underlying mucosal damage and lymphomagenesis in coeliac disease (CD). Methods: Enterocytes, IEL, and lamina propria mononuclear cells (LPMC) were isolated from 46 patients with uncomplicated CD (25 untreated and 21 treated) and 22 controls. IL-15 and IL-15Ra expression were determined by immunoblotting. Secretion of IL-15, interferon c (IFN-c), tumour necrosis factor a (TNF-a), and granzyme B into cell culture supernatants was assessed by ELISA. The ability of IL-15 to regulate IEL proliferation, perforin/granzyme dependent cytotoxicity, and apoptosis was tested by adding different combinations of IL-15, IL-15 blocking antibody, or chloroquine to IEL cultured alone or with Caco-2 cells as target. IL-15 mucosal levels were also determined by ELISA in five patients with complicated CD (two ulcerative jejunoileites, one refractory sprue, and two enteropathy associated T cell lymphomas) tested for T cell receptor c chain clonality. Results: IL-15 was overexpressed in untreated CD enterocytes and LPMC, and in the mucosa of complicated CD patients and uncomplicated untreated CD patients, where its levels correlated with the degree of mucosal damage. Enterocytes from untreated, but not treated, CD patients and controls secreted IL-15. Untreated CD IEL, characterised by higher IL-15Ra expression, showed increased proliferation, production of IFN-c and TNF-a, and perforin/granzyme dependent cytotoxicity, and a decreased propensity to apoptosis in response to IL-15. Conclusions: Our findings suggest that IL-15 plays a crucial role in the generation of epithelial damage in active CD. Its promotion of IEL survival in CD may predispose to the emergence of T cell clonal proliferations. Blocking IL-15, by suppressing uncontrolled IEL activation and survival, has the potential to provide new therapeutic tools to prevent tissue damage and lymphomagenesis in CD.

IL‐15 protects intestinal epithelial cells

“…This is in line with previous results characterizing IL-15 as a strong proinflammatory stimulus leading to increased IFN-c production by T lymphocytes in celiac disease [54,55].…”

Dietary gluten triggers concomitant activation of CD4 + and CD8 + αβ T cells and γδ T cells in celiac disease

“…However, we find that αEβ7 + CD38 + T cells express markers of differentiated effector cells before gut recruitment, and their appearance parallels the appearance of gluten-reactive CD4 + T cells in blood, rather than occurring later. Also, although increased numbers of IELs and mildly increased levels of IL-15 are present in celiac patients on a glutenfree diet (38), the recruitment we describe precedes significant intestinal inflammation and tissue damage, which only reliably occur histologically after 2-4 wk of continuous gluten exposure (39). These findings suggest that IELs in CD are not simply activated as bystanders as a consequence of gut inflammation.…”

Transglutaminase 2-specific coeliac disease autoantibodies induce morphological changes and signs of inflammation in the small-bowel mucosa of mice

“…For instance, no differences in the levels of IL-15, the innate immunity cytokine overexpressed in coeliac patients' small-intestinal epithelia and lamina propria (Di Sabatino et al 2006;Iacomino et al 2016;Maiuri et al 2000;Mention et al 2003),…”