The destruction of the intestinal epithelium by interleukin-15 (IL-15)-activated intraepithelial cytotoxic T lymphocytes (CTLs) is one of the main pathological events of coeliac disease — a T-cell-mediated disease of the small intestine induced by wheat gliadin. Two papers that were recently published in Immunity now provide insight into the mechanisms of this cytotoxicity: the triggering of NKG2D (natural-killer (NK) group 2, member D) on the cell-surface of intraepithelial CTLs by its ligand MICA (MHC-class-I-polypeptide-related sequence A) or MICB on the cell-surface of intestinal epithelial cells (IECs) initiates signalling pathways that lead to the killing of IECs, and this is coordinated by IL-15.

CTLs have been shown to express NK-cell receptors such as NKG2D, and signals transduced by these receptors can modulate the cytotoxicity of CTLs. So, Meresse et al. set out to investigate whether NKG2D expression by intraepithelial CTLs was important in coeliac disease. Intraepithelial CTLs isolated from biopsies of patients with active coeliac disease expressed markedly higher levels of NKG2D than the same cells from healthy individuals. In contrast to peripheral-blood-derived CTL clones (which cannot mediate target-cell lysis after stimulation through NKG2D alone), ligation of NKG2D alone was sufficient to induce lysis of target cells by intraepithelial CTLs from patients with active coeliac disease. Further analysis indicated that intraepithelial CTLs from healthy individuals could acquire this phenotype — high levels of NKG2D expression and the ability to lyse target cells after ligation of NKG2D alone — when cultured with IL-15. However, both exposure to IL-15 and recent stimulation through the T-cell receptor was required to enable peripheral-blood CD8+ memory T cells to elicit NKG2D-mediated lysis of target cells. These observations indicate that the high levels of IL-15 and the constant exposure to antigen in the intestine of patients with active coeliac disease are probably responsible for the NKG2D-mediated cytolytic phenotype of the intraepithelial CTLs isolated from these individuals.

IL-15 was shown to increase not only the expression of NKG2D but also the expression of signal-transduction adaptor molecule DAP10, further priming the cells to be responsive to NKG2D signalling. In the intestine of patients with active coeliac disease such signals could be provided by the NKG2D ligands MICA and/or MICB, the expression of which were found to be upregulated on the cell-surface of IECs from such individuals.

Similarly, in the second study, Hüe et al. observed that, compared with cells from healthy individuals, the level of expression of MICA was markedly increased on the cell-surface of IECs from patients with active coeliac disease. Furthermore, the level of MICA expression correlated with the severity of disease. In cultures of biopsies taken from coeliac patients on gluten-free diets (who are therefore free of active disease), wheat gliadin was shown to induce the expression of MICA by IECs. The gliadin peptide p31–49 (known to cause damage of the small intestine by itself) could also induce MICA expression by IECs, and this was abolished in the presence of IL-15-neutralizing antibody.

In contrast to the report of Meresse et al., Hüe et al. observed that intraepithelial CTLs from both healthy individuals and those with active coeliac disease expressed similar levels of NKG2D. Furthermore, when stimulated through NKG2D alone, intraepithelial CTL cell lines derived from patients with active coeliac disease could induce lysis of target cells only in certain situations — for example, if cells were recently exposed to high concentrations of IL-15. However, in all cases, NKG2D ligation markedly amplified CD3-mediated lysis of target cells, indicating a role for NKG2D signalling in the regulation of intraepithelial CTL cytotoxicity.

The results obtained from these studies indicate that NKG2D–MICA/MICB interactions are crucial for mediating destruction of IECs in active coeliac disease and that IL-15 regulates the frequency of this interaction. Further studies are required to confirm the precise relationship between IL-15, NKG2D and MICA/MICB in coeliac disease, but both groups suggest that targeting this axis could provide a novel therapy for coeliac disease.