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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) 1 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 1 T-cell response, we paired traditional IFN-g ELISpot with an assay to detect antigenspecific CD4 1 T cells that does not rely on tetramers, antigenstimulated 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 1 T cells were FOXP3 1 CD39 1 Treg cells, which reside within the pool of memory CD4 1 CD25 1 CD127 low CD45RO 1 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 1 CD39 1 Treg cells exhibited significantly reduced suppressive function compared with polyclonal Treg cells. Conclusion: This study provides the first estimation of FOXP3 1 CD39 1 Treg cell frequency within circulating gluten-specific CD4 1 T cells after oral gluten challenge of patients with celiac disease. FOXP3 1 CD39 1 Treg cells comprised a major proportion of all circulating gluten-specific CD4 1 T cells but had impaired suppressive function, indicating that Treg cell dysfunction might be a key contributor to disease pathogenesis. (
Cook et al. (Tue,) studied this question.