Tolerance to Ingested Deamidated Gliadin in Mice is Maintained by Splenic, Type 1 Regulatory T Cells

Pré, M. Fleur du; Kozijn, A.E.; Berkel, Lisette A. van; Borg, Mariëtte N. D. ter; Lindenbergh-Kortleve, Dicky J.; Jensen, Lise Torp; Kooy–Winkelaar, Yvonne; Koning, Frits; Boon, Louis; Nieuwenhuis, Edward E. S.; Sollid, Ludvig M.; Fugger, Lars; Samsom, Janneke N.

doi:10.1053/j.gastro.2011.04.048

Cited by 60 publications

(62 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Studies of mice have shown that Foxp3 + T REG specific to orally administrated Ags have a role in inducing oral tolerance (11,29). A study of HLA-DQ2.5/ gliadin-TCR double-transgenic mice that did not develop CD pathology found that T R1 -like, IL-10-producing cells were upregulated in response to orally administrated deamidated gliadin, implicating a role of these cells (30). A human study reported that there were HLA-DQ2.5-restricted, gluten-reactive T R1 cells present in gut biopsies of CD patients, but not control subjects (12).…”

Section: Discussionmentioning

confidence: 99%

Healthy HLA-DQ2.5+ Subjects Lack Regulatory and Memory T Cells Specific for Immunodominant Gluten Epitopes of Celiac Disease

Christophersen

Risnes

Bergseng

et al. 2016

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Celiac disease (CD) is an HLA-associated disorder characterized by a harmful T cell response to dietary gluten. It is not understood why most individuals who carry CD-associated HLA molecules, such as HLA-DQ2.5, do not develop CD despite continuous gluten exposure. In this study, we have used tetramers of HLA-DQ2.5 bound with immunodominant gluten epitopes to explore whether HLA-DQ2.5+ healthy individuals mount a specific CD4+ T cell response to gluten. We found that gluten tetramer-binding memory cells were rare in blood of healthy individuals. These cells showed lower tetramer-binding intensity and no signs of biased TCR usage compared with gluten tetramer-binding memory T cells from patients. After sorting and in vitro expansion, only 18% of the tetramer-binding memory cells from healthy subjects versus 79% in CD patients were gluten-reactive upon tetramer restaining. Further, T cell clones of tetramer-sorted memory cells of healthy individuals showed lower gluten-specific proliferative responses compared with those of CD patients, indicating that tetramer-binding memory cells in healthy control subjects may be cross-reactive T cells. In duodenal biopsy specimens of healthy control subjects, CD4+ T cells were determined not to be gluten reactive. Finally, gluten tetramer-binding cells of healthy individuals did not coexpress regulatory T cell markers (Foxp3+ CD25+) and cultured T cell clones did not express a cytokine profile that indicated immune-dampening properties. The results demonstrate that healthy HLA-DQ2.5+ individuals do not mount a T cell response to immunodominant gluten epitopes of CD.

show abstract

Section: Discussionmentioning

confidence: 99%

Healthy HLA-DQ2.5+ Subjects Lack Regulatory and Memory T Cells Specific for Immunodominant Gluten Epitopes of Celiac Disease

Christophersen

Risnes

Bergseng

et al. 2016

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Vaccine protein staining of cells from DQ2 transgene mice. Splenocytes from three DQ2 transgenic mice (31) were FcgR blocked by incubation with 30% heat-aggregated rat serum and 0.1 mg/ml 2.4G2 mAb (Fisher Scientific, Waltham, MA) and then stained sequentially with vaccine proteins (10 mg/ml), biotinylated HP6017 (1:2000) (042M4810; SigmaAldrich), and streptavidin-PE (2 mg/ml) (554061; BD Pharmingen). The staining solution also contained either FITC-conjugated mAb against CD19 (4 mg/ml) (35-0193; Tonbo Biosciences, San Diego, CA), PerCPCy5.5-conjugated mAb against CD11b (3 mg/ml) (66-0112-U100; Tonbo Biosciences), or allophycocyanin-conjugated mAb against CD11c (20-0114-U100; Tonbo Biosciences).…”

Section: Flow Cytometrymentioning

confidence: 99%

Antigen Targeting to Human HLA Class II Molecules Increases Efficacy of DNA Vaccination

Grødeland

Fredriksen²,

Løset

et al. 2016

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

It has been difficult to translate promising results from DNA vaccination in mice to larger animals and humans. Previously, DNA vaccines encoding proteins that target Ag to MHC class II (MHC-II) molecules on APCs have been shown to induce rapid, enhanced, and long-lasting Ag-specific Ab titers in mice. In this study, we describe two novel DNA vaccines that as proteins target HLA class II (HLA-II) molecules. These vaccine proteins cross-react with MHC-II molecules in several species of larger mammals. When tested in ferrets and pigs, a single DNA delivery with low doses of the HLA-II–targeted vaccines resulted in rapid and increased Ab responses. Importantly, painless intradermal jet delivery of DNA was as effective as delivery by needle injection followed by electroporation. As an indication that the vaccines could also be useful for human application, HLA-II–targeted vaccine proteins were found to increase human CD4+ T cell responses by a factor of ×103 in vitro. Thus, targeting of Ag to MHC-II molecules may represent an attractive strategy for increasing efficacy of DNA vaccines in larger animals and humans.

show abstract

“…Only a small fraction of individuals carrying the HLA-DQ2.5 or HLA-DQ8 haplotypes develop CD even if the risk is increased in individuals homozygous for HLA-DQ2.5 [10]. Moreover, no celiac-like enteropathy could be induced in humanized mice in which endogenous MHC class II molecules have been replaced by HLA-DQ8 or -DQ2.5, even if mice were also engineered to express a human CD4 (hCD4) molecule to facilitate T-cell interaction with HLA-DQ8 [11] or a T-cell receptor specific for a gluten peptide in the context of HLA-DQ2.5 [12,13]. One important pitfall was however the difficulty to activate the deamidation activity of TG2 in vivo in mice.…”

Section: The Hla-dq-restricted Anti-gluten Adaptive Immune Response Imentioning

confidence: 99%

“…One important pitfall was however the difficulty to activate the deamidation activity of TG2 in vivo in mice. This was notably the case in hDQ2 mice, which exclusively responded to deamidated gliadin [12,13]. Interestingly, a gluten-sensitive blistering skin disease reminiscent of dermatitis herpetiformis was observed in hCD4-DQ8 mice backcrossed on the autoimmune NOD background after intraperitoneal immunization and 2-5 months of gluten-containing diet [14].…”

Section: The Hla-dq-restricted Anti-gluten Adaptive Immune Response Imentioning

confidence: 99%

Interleukin-15, a Master Piece in the Immunological Jigsaw of Celiac Disease

Meresse

Korneychuk

Malamut³

et al. 2015

Dig Dis

View full text Add to dashboard Cite

Background: The immune response causing celiac disease (CD) depends on the activation of intestinal CD4+ T cells by gluten-derived peptides presented by HLA-DQ2 or HLA-DQ8 molecules, the main genetic risk factor. However, additional factors are necessary to impair immune tolerance to dietary gluten, to stimulate intraepithelial lymphocytes (IEL) and to induce intestinal damage. Key Messages: Current data point to a central role of interleukin-15 (IL-15). In situ and ex vivo studies indicate that IL-15 stimulates the accumulation and cytotoxic activation of CD8+ T IEL in active CD, and that of the malignant innate-like IEL in type II refractory CD (RCDII). Other studies show that IL-15 impairs the immunoregulatory control of effector T cells, notably CD8+. Recently, animal models have been designed to investigate the respective role of CD4+ T cells and IL-15 in CD. We discuss more particularly our results in such a model, which shows that IL-15 produced in excess in the intestine can cooperate with CD4+ T cells specific for a dietary antigen to trigger a celiac-like enteropathy. In this mouse model, CD4+ T cells activated by dietary ovalbumin secreted IL-2 which, along with IL-15, stimulated the expansion of noncognate intestinal cytotoxic CD8+ T cells containing large amounts of granzyme B. In the presence of IL-15, the latter cells did not respond to regulatory T cells, and accumulated in the intestine close to epithelial damage. Conclusion: On the basis of these data, we propose that, in CD, gluten-specific CD4+ T cells synthesize cytokines that synergize with IL-15 to license the expansion and activation of cytotoxic IEL, which drive tissue damage. We suggest that IL-15 is a meaningful therapeutic target, notably in patients with RCDII in which malignant IEL can respond to IL-15 independently of signals provided by CD4+ T cells.

show abstract

Tolerance to Ingested Deamidated Gliadin in Mice is Maintained by Splenic, Type 1 Regulatory T Cells

Cited by 60 publications

References 26 publications

Healthy HLA-DQ2.5+ Subjects Lack Regulatory and Memory T Cells Specific for Immunodominant Gluten Epitopes of Celiac Disease

Healthy HLA-DQ2.5+ Subjects Lack Regulatory and Memory T Cells Specific for Immunodominant Gluten Epitopes of Celiac Disease

Antigen Targeting to Human HLA Class II Molecules Increases Efficacy of DNA Vaccination

Interleukin-15, a Master Piece in the Immunological Jigsaw of Celiac Disease

Contact Info

Product

Resources

About