Circulating gluten-specific FOXP3+CD39+ regulatory T cells have impaired suppressive function in patients with celiac disease

Laura Cook, C. Mee Ling Munier, Nabila Seddiki, David J van Bockel, Noé Ontiveros, Melinda Y Hardy, Jana K. Gillies, Megan K. Levings, Hugh H. Reid, Jan Petersen, Jamie Rossjohn, Robert P Anderson, John Zaunders, Jason A Tye-Din, Anthony D Kelleher

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)1592-1603
Number of pages12
JournalJournal of Allergy and Clinical Immunology
Volume140
Issue number6
DOIs
Publication statusPublished - Dec 2017

Keywords

  • CD39
  • Celiac disease
  • Forkhead box protein 3
  • Gluten
  • OX40
  • Regulatory T cells

Cite this

Cook, L., Munier, C. M. L., Seddiki, N., van Bockel, D. J., Ontiveros, N., Hardy, M. Y., ... Kelleher, A. 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), 1592-1603. https://doi.org/10.1016/j.jaci.2017.02.015
Cook, Laura ; Munier, C. Mee Ling ; Seddiki, Nabila ; van Bockel, David J ; Ontiveros, Noé ; Hardy, Melinda Y ; Gillies, Jana K. ; Levings, Megan K. ; Reid, Hugh H. ; Petersen, Jan ; Rossjohn, Jamie ; Anderson, Robert P ; Zaunders, John ; Tye-Din, Jason A ; Kelleher, Anthony D. / Circulating gluten-specific FOXP3+CD39+ regulatory T cells have impaired suppressive function in patients with celiac disease. In: Journal of Allergy and Clinical Immunology. 2017 ; Vol. 140, No. 6. pp. 1592-1603.
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title = "Circulating gluten-specific FOXP3+CD39+ regulatory T cells have impaired suppressive function in 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+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.",
keywords = "CD39, Celiac disease, Forkhead box protein 3, Gluten, OX40, Regulatory T cells",
author = "Laura Cook and Munier, {C. Mee Ling} and Nabila Seddiki and {van Bockel}, {David J} and No{\'e} Ontiveros and Hardy, {Melinda Y} and Gillies, {Jana K.} and Levings, {Megan K.} and Reid, {Hugh H.} and Jan Petersen and Jamie Rossjohn and Anderson, {Robert P} and John Zaunders and Tye-Din, {Jason A} and Kelleher, {Anthony D}",
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Cook, L, Munier, CML, Seddiki, N, van Bockel, DJ, Ontiveros, N, Hardy, MY, Gillies, JK, Levings, MK, Reid, HH, Petersen, J, Rossjohn, J, Anderson, RP, Zaunders, J, Tye-Din, JA & Kelleher, AD 2017, 'Circulating gluten-specific FOXP3+CD39+ regulatory T cells have impaired suppressive function in patients with celiac disease', Journal of Allergy and Clinical Immunology, vol. 140, no. 6, pp. 1592-1603. https://doi.org/10.1016/j.jaci.2017.02.015

Circulating gluten-specific FOXP3+CD39+ regulatory T cells have impaired suppressive function in patients with celiac disease. / Cook, Laura; Munier, C. Mee Ling; Seddiki, Nabila; van Bockel, David J; Ontiveros, Noé; Hardy, Melinda Y; Gillies, Jana K.; Levings, Megan K.; Reid, Hugh H.; Petersen, Jan; Rossjohn, Jamie; Anderson, Robert P; Zaunders, John; Tye-Din, Jason A; Kelleher, Anthony D.

In: Journal of Allergy and Clinical Immunology, Vol. 140, No. 6, 12.2017, p. 1592-1603.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Circulating gluten-specific FOXP3+CD39+ regulatory T cells have impaired suppressive function in patients with celiac disease

AU - Cook, Laura

AU - Munier, C. Mee Ling

AU - Seddiki, Nabila

AU - van Bockel, David J

AU - Ontiveros, Noé

AU - Hardy, Melinda Y

AU - Gillies, Jana K.

AU - Levings, Megan K.

AU - Reid, Hugh H.

AU - Petersen, Jan

AU - Rossjohn, Jamie

AU - Anderson, Robert P

AU - Zaunders, John

AU - Tye-Din, Jason A

AU - Kelleher, Anthony D

PY - 2017/12

Y1 - 2017/12

N2 - 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.

AB - 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.

KW - CD39

KW - Celiac disease

KW - Forkhead box protein 3

KW - Gluten

KW - OX40

KW - Regulatory T cells

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DO - 10.1016/j.jaci.2017.02.015

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JF - Journal of Allergy and Clinical Immunology

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