Circulating Gluten-Specific FOXP3+CD39+ Regulatory T Cells Have Impaired Suppressive Function in Celiac Disease

Publication date: Available online 8 March 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Laura Cook, C. Mee Ling Munier, Nabila Seddiki, David van Bockel, Noé Ontiveros, Melinda Y. Hardy, Jana K. Gillies, Megan K. Levings, Hugh Reid, Jan Peterson, Jamie Rossjohn, Robert P. Anderson, John Zaunders, Jason A. Tye-Din, Anthony D. Kelleher
BackgroundCeliac 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.ObjectiveTo define if celiac disease patients have a dysfunction or lack of gluten-specific FOXP3⁺ Tregs.MethodsTreated 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-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 co-expression of CD25 and OX40 (CD134).ResultsThe 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⁺CD127^lowCD45RO⁺ 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.ConclusionThis 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.

Teaser

We performed a novel study of gluten-specific FOXP3⁺ Tregs in patients with celiac disease and found that, although these cells comprise the majority of circulating gluten-specific CD4⁺ T-cells, they have impaired suppressive function.


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