HLA-DQ2-restricted gluten-reactive T cells produce IL-21 but not IL-17 or IL-22

Abstract

We have analyzed the production of the effector cytokines interleukin (IL)-17, IL-21, and IL-22 in gluten-reactive CD4(+) T cells of celiac disease patients, either cultured from small intestinal biopsies or isolated from peripheral blood after an oral gluten challenge. Combining intracellular cytokine staining with DQ2-α-II gliadin peptide tetramer staining of intestinal polyclonal T-cell lines, we found that gluten-specific T cells produced interferon-γ (IFN-γ) and IL-21, but not IL-17 or IL-22, even if other T cells of the same lines produced these cytokines. Similarly, in DQ2-α-II-specific T cells in peripheral blood of gluten-challenged patients, very few stained for intracellular IL-17, whereas many cells stained for IFN-γ. We conclude that gluten-reactive T cells produce IL-21 and IFN-γ, but not IL-17. Their production of IL-21 suggests a role for this cytokine in the pathogenesis of celiac disease.

CD4 T-cell cytokines synergize to induce proliferation of malignant and nonmalignant innate intraepithelial lymphocytes

“…The same was true for IL-15, which is not produced by T cells. In short, these findings are consistent with previous reports on the cytokine profiles of CD4 + T cells in CD (19,30,31,(33)(34)(35)(36)(37)(38)(39)(40), and identify additional cytokines produced by a gluten-specific CD4 + T-cell clone.…”

“…Analysis of three biological replicates showed consistent activation-induced up-regulation of 141 transcripts, 31 of which encoded secreted proteins (Table 1). These included transcripts encoding cytokines previously reported for gluten-specific CD4 + T cells, such as IFNγ, TNF, IL-10, and IL-21 (30,31), as well as cytokines not commonly associated with CD, such as IL-22 (30) and amphiregulin (AREG), both of which are involved in the homeostasis of intestinal epithelial cells (IECs). Next, we analyzed supernatants from CD4 + T-cell clone L10 by mass spectrometry (MS).…”

“…TNF, IL-2, and IL-21 were reported to be produced by gluten-activated CD4 + T-cell clones on activation (19,30,31) and to be elevated in CD biopsy specimens exposed to gluten in vivo or ex vivo (33,34,39). In contrast, IL-17A is not produced by gluten-specific clones (30), but some studies have shown that it is elevated in gluten-exposed biopsy specimens (32,45). This finding suggests that cytokines produced by gluten-specific CD4 + T cells trigger IL-17 production by other immune cells (32).…”

“…Experiments examining the expression of CD4 + T-cell cytokine transcripts and proteins in patient biopsy specimens and biopsy-derived gluten-specific CD4 + T cells focused on IFNG, TNF, IL2 (31, 33, 35, 36), and, more recently, on IL17, IL21, and IL22 (30,(37)(38)(39)(40). TNF, IL-2, and IL-21 were reported to be produced by gluten-activated CD4 + T-cell clones on activation (19,30,31) and to be elevated in CD biopsy specimens exposed to gluten in vivo or ex vivo (33,34,39). In contrast, IL-17A is not produced by gluten-specific clones (30), but some studies have shown that it is elevated in gluten-exposed biopsy specimens (32,45).…”

Shared genetics in coeliac disease and other immune-mediated diseases

“…The close association between certain HLA alleles and the development of CD can be explained by the high affinity of the ab heterodimers of HLA-DQ2 and HLA-DQ8 for the binding of gliadin-derived peptides, with or without modification by the tTG enzyme [26]; homozygosity for HLA-DQ2.5 has the highest affinity for gluten [27,28]. The resulting immune response leads to the generation of disease-specific antibodies and the secretion of proinflammatory cytokines, such as interleukin (IL)1b, IL4, IL6, IL8, IL10, IL15, IL17A, IL21, tumour necrosis factor (TNF)a and interferon (INF)c, which cause intestinal mucosal atrophy and the consequent clinical manifestations [29].…”