Gluten specific, HLA-DQ restricted T cells from coeliac mucosa produce cytokines with Th1 or Th0 profile dominated by interferon gamma.

Nilsen, Ellen M.; Lundin, Knut E.A.; Krajči, Peter; Scott, Helge; Sollid, Ludvig M.; Brandtzæg, Per

doi:10.1136/gut.37.6.766

Cited by 326 publications

(233 citation statements)

References 52 publications

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“…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.…”

Section: Resultssupporting

confidence: 82%

“…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).…”

Section: Resultsmentioning

confidence: 99%

“…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).…”

Section: Discussionmentioning

confidence: 99%

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

Kooy–Winkelaar

Bouwer

Janssen

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Refractory celiac disease type II (RCDII) is a severe complication of celiac disease (CD) characterized by the presence of an enlarged clonal population of innate intraepithelial lymphocytes (IELs) lacking classical B-, T-, and natural killer (NK)-cell lineage markers (Lin − IELs) in the duodenum. In ∼50% of patients with RCDII, these Lin − IELs develop into a lymphoma for which no effective treatment is available. Current evidence indicates that the survival and expansion of these malignant Lin − IELs is driven by epithelial cell-derived IL-15. Like CD, RCDII is strongly associated with HLA-DQ2, suggesting the involvement of HLA-DQ2-restricted gluten-specific CD4 + T cells. We now show that gluten-specific CD4 + T cells isolated from CD duodenal biopsy specimens produce cytokines able to trigger proliferation of malignant Lin − IEL lines as powerfully as IL-15. Furthermore, we identify TNF, IL-2, and IL-21 as CD4 + T-cell cytokines that synergistically mediate this effect. Like IL-15, these cytokines were found to increase the phosphorylation of STAT5 and Akt and transcription of antiapoptotic mediator bcl-x L . Several small-molecule inhibitors targeting the JAK/STAT pathway blocked proliferation elicited by IL-2 and IL-15, but only an inhibitor targeting the PI3K/Akt/mTOR pathway blocked proliferation induced by IL-15 as well as the CD4 + T-cell cytokines. Confirming and extending these findings, TNF, IL-2, and IL-21 also synergistically triggered the proliferation of freshly isolated Lin − IELs and CD3 − CD56 + IELs (NK-IELs) from RCDII as well as non-RCDII duodenal biopsy specimens. These data provide evidence implicating CD4 + T-cell cytokines in the pathogenesis of RCDII. More broadly, they suggest that adaptive immune responses can contribute to innate IEL activation during mucosal inflammation.celiac disease | refractory celiac disease | enteropathy-associated T-cell lymphoma | small-molecule inhibitor | intraepithelial lymphocyte

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Section: Resultssupporting

confidence: 82%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Kooy–Winkelaar

Bouwer

Janssen

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…5 In particular, in the lamina propria, gliadin peptides activate tissue TG2, the coeliac autoantigen, 6 which selectively deamidates the gluten protein resulting in CD4 þ T-cell activation. These cells release mediators, such as interferon-g (IFN-g), 7 tumour necrosis factor-a (TNF-a) 7 and interleukin (IL)-10, 8 which ultimately cause tissue damage and the production of autoantibodies. During the innate immune response in CD, the expression of IL-15 is upregulated in the intestinal mucosa, resulting in the activation of cytotoxicity directed against enterocytes.…”

mentioning

confidence: 99%

Gluten induces coeliac-like disease in sensitised mice involving IgA, CD71 and transglutaminase 2 interactions that are prevented by probiotics

Papista

Gerakopoulos

Kourelis

et al. 2012

Laboratory Investigation

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Coeliac disease (CD) is a malabsorptive enteropathy resulting from intolerance to gluten. Environmental factors and the microbiota are suggested to have critical roles in the onset of CD. The CD71 IgA receptor on epithelial cells is responsible for abnormal retrotranscytosis of IgA-gluten peptide complexes from the intestinal lumen into the lamina propria, inducing intestinal inflammation. However, understanding the role of gluten in the CD physiopathology has been hindered by the absence of relevant animal models. Here, we generated a mouse model for CD to study the factors controlling its pathogenesis as well as to investigate the influence of oral delivery of probiotics on disease development. Gluten sensitivity was established by feeding three generations of BALB/c mice a gluten-free diet (GÀ) followed by gluten challenge (G þ ) for 30 days. The G þ mice developed villous atrophy, crypt hyperplasia and infiltration of T cells and macrophages in the small intestine. Inflammation was associated with an overexpression of CD71 on the apical side of enterocytes and an increase of plasma cells producing IgA, which colocalised with the CD71. Moreover, IgA colocalised with the transglutaminase 2 (TG2), the production of which was increased in the lamina propria of G þ mice. These mice displayed increased production of cyclooxygenase-2 (COX-2), pro-inflammatory cytokines and IL-15, as well as anti-gliadin and anti-TG2 autoantibodies. The commensal flora-isolated presumptive probiotic Saccharomyces boulardii KK1 strain hydrolysed the 28-kDa a-gliadin fraction, and its oral delivery in G þ mice improved enteropathy development in association with decrease of epithelial cell CD71 expression and local cytokine production. In conclusion, the G þ BALB/c mouse represents a new mouse model for human CD based on histopathological features and expression of common biomarkers. The selected probiotic treatment reversing disease development will allow the study of the role of probiotics as a new therapeutic approach of CD.

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“…The antigen-presenting cells present deamidated gliadin peptides to HLA-DQ2-or HLA-DQ8-restricted populations of CD4 1 T cells that then become activated and differentiate into Th1 and Th2 cells. 42 These cells release mediators, such as interferon-c and tumor necrosis factor-a, 45 that ultimately lead to tissue damage and the production of autoantibodies. 46 During the innate immune response in CD, IL-15 is upregulated on the surface of enterocytes.…”

Section: Iga Dysfunctions In Intestinal and Renall Diseaseszmentioning

confidence: 99%

Dysfunctions of the Iga system: a common link between intestinal and renal diseases

2011

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Gluten specific, HLA-DQ restricted T cells from coeliac mucosa produce cytokines with Th1 or Th0 profile dominated by interferon gamma.

Cited by 326 publications

References 52 publications

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

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

Gluten induces coeliac-like disease in sensitised mice involving IgA, CD71 and transglutaminase 2 interactions that are prevented by probiotics

Dysfunctions of the Iga system: a common link between intestinal and renal diseases

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