Circulating gluten-specific FOXP3+CD39+ regulatory t cells have impaired suppressive function in Celiac Disease

Cook, L; Munier, CM; Seddiki, N; van Bockel, D; Ontiveros, N; Hardy, MY; Gillies, JK; Levings, MK; Reid, H; Peterson, J; Rossjohn, J; Anderson, RP; Zaunders, J; Tye-Din, JA; Kelleher, AD

Author(s): Cook, L; Munier, CM; Seddiki, N; van Bockel, D; Ontiveros, N; Hardy, MY; Gillies, JK; Levings, MK; Reid, H; Peterson, J; Rossjohn, J; Anderson, RP; Zaunders, J; Tye-Din, JA; Kelleher, AD;
Details: Publication Year 2017-12,Volume 140,Issue #6,Page 1592-1603.e8
Journal Title: Journal of Allergy and Clinical Immunology
Publication Type: Journal Article
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 celiac disease has been well characterized, the role of regulatory T-cells (Tregs) in the loss of tolerance to gluten remains poorly understood. OBJECTIVE: To define if celiac disease patients have a dysfunction or lack of gluten-specific FOXP3+ Tregs. METHODS: Treated celiac disease patients underwent oral wheat challenge to stimulate re-circulation of gluten-specific T-cells. Peripheral blood was collected pre- and post-challenge. In order to comprehensively measure the gluten-specific CD4+ T-cell response, we paired traditional IFN-gamma 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 co-expression of CD25 and OX40 (CD134). RESULTS: The number of circulating gluten-specific Tregs and effector T-cells both increased significantly post 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+ Tregs, which reside within the pool of memory CD4+CD25+CD127lowCD45RO+ Tregs. Although we observed normal suppressive function in peripheral polyclonal Tregs from celiac patients, after a short in vitro expansion the gluten-specific FOXP3+CD39+ Tregs exhibited significantly reduced suppressive function compared to polyclonal Tregs. CONCLUSION: This study provides the first estimation of FOXP3+CD39+ Treg frequency within circulating gluten-specific CD4+ T-cells following oral gluten challenge of celiac patients. FOXP3+CD39+ Tregs comprised a major proportion of all circulating gluten-specific CD4+ T-cells but had impaired suppressive function, indicating that Treg dysfunction may be a key contributor to disease pathogenesis.
Publisher: Elsevier
Research Division(s): Immunology
PubMed ID: 28283419
Publisher's Version: https://doi.org/10.1016/j.jaci.2017.02.015
Open Access at Publisher's Site: http://dx.doi.org/10.1016/j.jaci.2017.02.015
NHMRC Grants: NHMRC/510448, NHMRC/1085875, NHMRC/1085875,
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2017-04-12 10:42:06

Last Modified: 2017-12-07 01:02:37