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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:140

Article

Cook, Laura^1,2,11  Munier, C. Mee Ling¹  Seddiki, Nabila^1,2,12,13  van Bockel, David¹  Ontiveros, Noe^3,4  Hardy, Melinda Y.^3,4  Gillies, Jana K.⁵  Levings, Megan K.⁵  Reid, Hugh H.^6,7  Petersen, Jan^6,7  Rossjohn, Jamie^6,7,8  Anderson, Robert P.^3,4,9  Zaunders, John J.^1,2  Tye-Din, Jason A.^3,4,10  Kelleher, Anthony D.^1,2 

[1] UNSW Sydney, Immunovirol & Pathogenesis Program, Kirby Inst, Sydney, NSW, Australia

[2] St Vincents Hosp, St Vincents Ctr Appl Med Res, Sydney, NSW, Australia

[3] Walter & Eliza Hall Inst Med Res, Div Immunol, Parkville, Vic, Australia

[4] Univ Melbourne, Dept Med Biol, Parkville, Vic, Australia

[5] Univ British Columbia, Dept Surg, Vancouver, BC, Canada

[6] Monash Univ, Infect & Immun Program, Dept Biochem & Mol Biol, Biomed Discovery Inst, Clayton, Vic, Australia

[7] Monash Univ, Australian Res Council, Ctr Excellence Adv Mol Imaging, Clayton, Vic, Australia

[8] Cardiff Univ, Sch Med, Inst Infect & Immun, Heath Pk, Cardiff, S Glam, Wales

[9] ImmusanT, Cambridge, England

[10] Royal Melbourne Hosp, Dept Gastroenterol, Parkville, Vic, Australia

[11] Univ British Columbia, Dept Med, Vancouver, BC, Canada

[12] INSERM, U955, Creteil, France

[13] UPEC, Vaccine Res Inst, Creteil, France

关键词: Regulatory T cells;    CD39;    forkhead box protein 3;    celiac disease;    gluten;    OX40;   

DOI  :  10.1016/j.jaci.2017.02.015

来源: Elsevier

【 摘 要 】

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-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 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.

【 授权许可】

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