Circulating gluten-specific FOXP3+CD39+ regulatory T cells have impaired suppressive function in patients with celiac disease.
Laura Cook,Laura Cook,C Mee Ling Munier,Nabila Seddiki,Nabila Seddiki,David van Bockel,Noé Ontiveros,Noé Ontiveros,Melinda Y Hardy,Melinda Y Hardy,Jana Gillies,Megan K. Levings,Hugh H. Reid,Hugh H. Reid,Jan Petersen,Jan Petersen,Jamie Rossjohn,Jamie Rossjohn,Jamie Rossjohn,Robert P. Anderson,Robert P. Anderson,John Zaunders,John Zaunders,Jason A. Tye-Din,Jason A. Tye-Din,Jason A. Tye-Din,Anthony D. Kelleher,Anthony D. Kelleher +27 more
TLDR
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.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 + CD127 low CD45RO + 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.read more
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Guidelines for the use of flow cytometry and cell sorting in immunological studies
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References
More filters
Journal ArticleDOI
Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells
Nabila Seddiki,Nabila Seddiki,Brigitte Santner-Nanan,Jeff Martinson,John Zaunders,Sarah C. Sasson,Alan L. Landay,Michael J. Solomon,Warwick Selby,Stephen I. Alexander,Ralph Nanan,Anthony D. Kelleher,Barbara Fazekas de St Groth +12 more
TL;DR: Cell surface expression of CD127 allows accurate estimation of T reg cell numbers and isolation of pure populations for in vitro studies and should contribute to the understanding of regulatory abnormalities in immunopathic diseases.
Journal ArticleDOI
Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease
Øyvind Molberg,Stephen N. McAdam,Roman Körner,Hanne Quarsten,Christel Kristiansen,Lars Madsen,Lars Fugger,Lars Fugger,Helge Scott,Ove Norén,Peter Roepstorff,Knut E.A. Lundin,Hans Sjöström,Ludvig M. Sollid +13 more
TL;DR: Evidence is provided for a new role of Transglutaminase in the common, HLA-DQ2 (and DQ8) associated celiac disease and it is demonstrated that TGase mediates its effect through an ordered and specific deamidation of gliadins.
Journal ArticleDOI
Oral tolerance: Basic mechanisms and applications of oral tolerance
TL;DR: A major avenue being investigated for the treatment of autoimmunity is the induction of Tregs and mucosal tolerance represents a non‐toxic, physiologic approach to reach this goal.
Journal ArticleDOI
Molecular Basis of Celiac Disease
TL;DR: CD provides a good model for HLA-associated diseases, and insight into the mechanism of this disease may well shed light on oral tolerance in humans, as well as explaining the occurrence of gluten-dependent tTG autoantibodies that is a characteristic feature of active CD.
Journal ArticleDOI
In vivo antigen challenge in celiac disease identifies a single transglutaminase-modified peptide as the dominant A-gliadin T-cell epitope.
TL;DR: Fresh peripheral blood lymphocytes from individual subjects undergoing short-term antigen challenge and tissue transglutaminase-treated, overlapping synthetic peptides spanning A-gliadin are used to demonstrate a transient, disease-specific, DQ2-restricted, CD4 T-cell response to a single dominant epitope.