Impaired Control of Effector T Cells by Regulatory T Cells: A Clue to Loss of Oral Tolerance and Autoimmunity in Celiac Disease?

Nadia Belhadj Hmida (1) , Mélika Ben Ahmed (1) , Amel Moussa (2, 3) , Majd Ben Rejeb (2) , Yosra Said (3, 2) , Nadia Kourda (3, 4) , Bertrand Meresse (5) , Maha Abdeladhim (1) , Hechmi Louzir (1) , Nadine Cerf-Bensussan (5)

1 Laboratoire d'immunologie clinique [Institut Pasteur de Tunis]
2 Département de Gastroentérologie et hépatologie
3 UTM - Université de Tunis El Manar
4 Département de Pathologie
5 UMR_S 793 - Interactions de l'épithelium intestinal et du système immunitaire

OBJECTIVES:Regulatory T cells (Tregs) are instrumental for tolerance to self-antigens and dietary proteins. We have previously shown that interleukin (IL)-15, a cytokine overexpressed in the intestine of patients with celiac disease (CD), does not impair the generation of functional Tregs but renders human T cells resistant to Treg suppression. Treg numbers and responses of intestinal and peripheral T lymphocytes to suppression by Tregs were therefore compared in CD patients and controls.METHODS:Intraepithelial lymphocytes (IELs) and lamina propria lymphocytes (LPLs) were isolated from duodenal biopsy specimens of CD patients and controls. Concomitantly, CD4+CD25+ T lymphocytes (Tregs) were purified from blood. Responses of IELs and of LPLs, and peripheral lymphocytes (PBLs) to suppression by Tregs were tested by analyzing anti-CD3-induced proliferation and interferon (IFN)-γ production in the presence or absence of peripheral Tregs. Lamina propria and peripheral CD4+CD25+FOXP3+ T cells were assessed by flow cytometry.RESULTS:Although percentages of CD4+CD25+FOXP3+ LPLs were significantly increased in patients with active CD, proliferation and IFN-γ production of intestinal T lymphocytes were significantly less inhibited by autologous or heterologous Tregs in CD patients than in controls (P<0.01). In all tested CD patients, IEL were unable to respond to Tregs. Resistance of LPLs and PBLs to Treg suppression was observed in patients with villous atrophy who had significantly enhanced serum levels of IL-15 compared with patients without villous atrophy and controls.CONCLUSIONS:Our results indicate that effector T lymphocytes from active CD become resistant to suppression by Tregs. This resistance might cause loss of tolerance to gluten, but also to self-antigens.Am J Gastroenterol advance online publication, 22 November 2011; doi:10.1038/ajg.2011.397.

Mots clés: Celiac disease; Regulatory T cells; IL-15

Domaines: Hépatologie et Gastroentérologie

Nadia Belhadj Hmida, Mélika Ben Ahmed, Amel Moussa, Majd Ben Rejeb, Yosra Said, et al.. Impaired Control of Effector T Cells by Regulatory T Cells: A Clue to Loss of Oral Tolerance and Autoimmunity in Celiac Disease?. The American Journal of Gastroenterology, 2011, epub ahead of print. ⟨10.1038/ajg.2011.397⟩. ⟨pasteur-00658348⟩