Cook, Laura, Munier, C. Mee Ling, Seddiki, Nabila, van Bockel, David, Ontiveros, Noé, Hardy, Melinda Y., Gillies, Jana K., Levings, Megan K., Reid, Hugh H., Petersen, Jan, Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522, Anderson, Robert P., Zaunders, John J., Tye-Din, Jason A. and Kelleher, Anthony D. 2017. Circulating gluten-specific FOXP3 + CD39 + regulatory T cells have impaired suppressive function in patients with celiac disease. Journal of Allergy and Clinical Immunology 140 (6) , pp. 1592-1603. 10.1016/j.jaci.2017.02.015 |
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Abstract
Background Celiac disease is a chronic immune-mediated inflammatory disorder of the gut triggered by dietary gluten. Although the effector T-cell response in patients with celiac disease has been well characterized, the role of regulatory T (Treg) cells in the loss of tolerance to gluten remains poorly understood. Objective We sought to define whether patients with celiac disease have a dysfunction or lack of gluten-specific forkhead box protein 3 (FOXP3)+ Treg cells. Methods Treated patients with celiac disease underwent oral wheat challenge to stimulate recirculation of gluten-specific T cells. Peripheral blood was collected before and after challenge. To comprehensively measure the gluten-specific CD4+ T-cell response, we paired traditional IFN-γ ELISpot with an assay to detect antigen-specific CD4+ T cells that does not rely on tetramers, antigen-stimulated cytokine production, or proliferation but rather on antigen-induced coexpression of CD25 and OX40 (CD134). Results Numbers of circulating gluten-specific Treg cells and effector T cells both increased significantly after oral wheat challenge, peaking at day 6. Surprisingly, we found that approximately 80% of the ex vivo circulating gluten-specific CD4+ T cells were FOXP3+CD39+ Treg cells, which reside within the pool of memory CD4+CD25+CD127lowCD45RO+ Treg cells. Although we observed normal suppressive function in peripheral polyclonal Treg cells from patients with celiac disease, after a short in vitro expansion, the gluten-specific FOXP3+CD39+ Treg cells exhibited significantly reduced suppressive function compared with polyclonal Treg cells. Conclusion This study provides the first estimation of FOXP3+CD39+ Treg cell frequency within circulating gluten-specific CD4+ T cells after oral gluten challenge of patients with celiac disease. FOXP3+CD39+ Treg cells comprised a major proportion of all circulating gluten-specific CD4+ T cells but had impaired suppressive function, indicating that Treg cell dysfunction might be a key contributor to disease pathogenesis.
Item Type: | Article |
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Date Type: | Publication |
Status: | Published |
Schools: | Medicine |
Additional Information: | This is an open access article under the CC BY-NC-ND license |
Publisher: | Elsevier |
ISSN: | 0091-6749 |
Date of First Compliant Deposit: | 10 July 2017 |
Date of Acceptance: | 16 February 2017 |
Last Modified: | 06 May 2023 00:30 |
URI: | https://orca.cardiff.ac.uk/id/eprint/102239 |
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