Potential impact of celiac disease genetic risk factors on T cell receptor signaling in gluten-specific CD4+ T cells

Abstract Celiac disease is an auto-immune disease in which an immune response to dietary gluten leads to inflammation and subsequent atrophy of small intestinal villi, causing severe bowel discomfort and malabsorption of nutrients. The major instigating factor for the immune response in celiac disea...

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Autores principales:	Olivier B. Bakker, Aarón D. Ramírez-Sánchez, Zuzanna A. Borek, Niek de Klein, Yang Li, Rutger Modderman, Yvonne Kooy-Winkelaar, Marie K. Johannesen, Filomena Matarese, Joost H. A. Martens, Vinod Kumar, Jeroen van Bergen, Shuo-Wang Qiao, Knut E. A. Lundin, Ludvig M. Sollid, Frits Koning, Cisca Wijmenga, Sebo Withoff, Iris H. Jonkers
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/66b9019aaac7432d846ad8c14c396c51
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spelling	oai:doaj.org-article:66b9019aaac7432d846ad8c14c396c512021-12-02T13:41:34ZPotential impact of celiac disease genetic risk factors on T cell receptor signaling in gluten-specific CD4+ T cells10.1038/s41598-021-86612-52045-2322https://doaj.org/article/66b9019aaac7432d846ad8c14c396c512021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-86612-5https://doaj.org/toc/2045-2322Abstract Celiac disease is an auto-immune disease in which an immune response to dietary gluten leads to inflammation and subsequent atrophy of small intestinal villi, causing severe bowel discomfort and malabsorption of nutrients. The major instigating factor for the immune response in celiac disease is the activation of gluten-specific CD4+ T cells expressing T cell receptors that recognize gluten peptides presented in the context of HLA-DQ2 and DQ8. Here we provide an in-depth characterization of 28 gluten-specific T cell clones. We assess their transcriptional and epigenetic response to T cell receptor stimulation and link this to genetic factors associated with celiac disease. Gluten-specific T cells have a distinct transcriptional profile that mostly resembles that of Th1 cells but also express cytokines characteristic of other types of T-helper cells. This transcriptional response appears not to be regulated by changes in chromatin state, but rather by early upregulation of transcription factors and non-coding RNAs that likely orchestrate the subsequent activation of genes that play a role in immune pathways. Finally, integration of chromatin and transcription factor binding profiles suggest that genes activated by T cell receptor stimulation of gluten‑specific T cells may be impacted by genetic variation at several genetic loci associated with celiac disease.Olivier B. BakkerAarón D. Ramírez-SánchezZuzanna A. BorekNiek de KleinYang LiRutger ModdermanYvonne Kooy-WinkelaarMarie K. JohannesenFilomena MatareseJoost H. A. MartensVinod KumarJeroen van BergenShuo-Wang QiaoKnut E. A. LundinLudvig M. SollidFrits KoningCisca WijmengaSebo WithoffIris H. JonkersNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Olivier B. Bakker Aarón D. Ramírez-Sánchez Zuzanna A. Borek Niek de Klein Yang Li Rutger Modderman Yvonne Kooy-Winkelaar Marie K. Johannesen Filomena Matarese Joost H. A. Martens Vinod Kumar Jeroen van Bergen Shuo-Wang Qiao Knut E. A. Lundin Ludvig M. Sollid Frits Koning Cisca Wijmenga Sebo Withoff Iris H. Jonkers Potential impact of celiac disease genetic risk factors on T cell receptor signaling in gluten-specific CD4+ T cells
description	Abstract Celiac disease is an auto-immune disease in which an immune response to dietary gluten leads to inflammation and subsequent atrophy of small intestinal villi, causing severe bowel discomfort and malabsorption of nutrients. The major instigating factor for the immune response in celiac disease is the activation of gluten-specific CD4+ T cells expressing T cell receptors that recognize gluten peptides presented in the context of HLA-DQ2 and DQ8. Here we provide an in-depth characterization of 28 gluten-specific T cell clones. We assess their transcriptional and epigenetic response to T cell receptor stimulation and link this to genetic factors associated with celiac disease. Gluten-specific T cells have a distinct transcriptional profile that mostly resembles that of Th1 cells but also express cytokines characteristic of other types of T-helper cells. This transcriptional response appears not to be regulated by changes in chromatin state, but rather by early upregulation of transcription factors and non-coding RNAs that likely orchestrate the subsequent activation of genes that play a role in immune pathways. Finally, integration of chromatin and transcription factor binding profiles suggest that genes activated by T cell receptor stimulation of gluten‑specific T cells may be impacted by genetic variation at several genetic loci associated with celiac disease.
format	article
author	Olivier B. Bakker Aarón D. Ramírez-Sánchez Zuzanna A. Borek Niek de Klein Yang Li Rutger Modderman Yvonne Kooy-Winkelaar Marie K. Johannesen Filomena Matarese Joost H. A. Martens Vinod Kumar Jeroen van Bergen Shuo-Wang Qiao Knut E. A. Lundin Ludvig M. Sollid Frits Koning Cisca Wijmenga Sebo Withoff Iris H. Jonkers
author_facet	Olivier B. Bakker Aarón D. Ramírez-Sánchez Zuzanna A. Borek Niek de Klein Yang Li Rutger Modderman Yvonne Kooy-Winkelaar Marie K. Johannesen Filomena Matarese Joost H. A. Martens Vinod Kumar Jeroen van Bergen Shuo-Wang Qiao Knut E. A. Lundin Ludvig M. Sollid Frits Koning Cisca Wijmenga Sebo Withoff Iris H. Jonkers
author_sort	Olivier B. Bakker
title	Potential impact of celiac disease genetic risk factors on T cell receptor signaling in gluten-specific CD4+ T cells
title_short	Potential impact of celiac disease genetic risk factors on T cell receptor signaling in gluten-specific CD4+ T cells
title_full	Potential impact of celiac disease genetic risk factors on T cell receptor signaling in gluten-specific CD4+ T cells
title_fullStr	Potential impact of celiac disease genetic risk factors on T cell receptor signaling in gluten-specific CD4+ T cells
title_full_unstemmed	Potential impact of celiac disease genetic risk factors on T cell receptor signaling in gluten-specific CD4+ T cells
title_sort	potential impact of celiac disease genetic risk factors on t cell receptor signaling in gluten-specific cd4+ t cells
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/66b9019aaac7432d846ad8c14c396c51
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Potential impact of celiac disease genetic risk factors on T cell receptor signaling in gluten-specific CD4+ T cells

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