Colon/Small Bowel

Subject Category: Colon/Small Bowel

Am J Gastroenterol 2011; 106:1308–1317; doi:10.1038/ajg.2011.80; published online 5 April 2011

IL-15 Interferes With Suppressive Activity of Intestinal Regulatory T Cells Expanded in Celiac Disease

Delia Zanzi MS1,2,5, Rosita Stefanile PhD3,5, Sara Santagata PhD1, Laura Iaffaldano MS1, Gaetano Iaquinto MD4, Nicola Giardullo MD4, Giuliana Lania MS1, Ilaria Vigliano MS1, Aufiero Rotondi Vera BS3, Katia Ferrara BS1, Salvatore Auricchio MD1,2, Riccardo Troncone MD1,2 and Giuseppe Mazzarella MS2,3

  1. 1Department of Paediatrics University Federico II, Naples, Italy
  2. 2European Laboratory for the Investigation of Food-Induced Diseases, University Federico II, Naples, Italy
  3. 3Institute of Food Science, CNR, Immunobiology, Avellino, Italy
  4. 4Gastroenterology and Digestive Endoscopy Service, San G. Moscati Hospital, Avellino, Italy
  5. 5These authors contributed equally to this manuscript and should be considered joint first authors

Correspondence: Giuseppe Mazzarella, Institute of Food Science, CNR, Immunobiology, via Roma 64, Avellino, Italy. E-mail: gmazzarella@isa.cnr.it

Received 30 April 2010; Accepted 4 February 2011; Published online 5 April 2011.

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Abstract

OBJECTIVES:

 

Celiac disease (CD) is a condition in which the regulation of the mucosal immune response to dietary gliadin might be altered. The transcription factor forkhead box P3 (Foxp3) has been identified as a marker of a subset of regulatory T cells (Treg). In this study, we have investigated the presence and the suppressive function of Treg cells in the celiac small intestinal mucosa, their correlation with the disease state, and the inducibility by gliadin in an organ culture system; moreover, we tried to define whether interleukin 15 (IL-15), overexpressed in CD, could influence the regulatory activity of such cells.

METHODS:

 

The expression of Foxp3, CD3, CD4, and CD8 were analyzed by immunohistochemistry and flow cytometry in duodenal biopsies taken from patients with untreated CD, treated CD, and from non-CD controls, as well as in vitro cultured biopsy samples from treated CD patients, upon challenge with gliadin. Furthermore, we analyzed the suppressive function of CD4+CD25+ T cells, isolated from untreated CD biopsy samples, on autologous responder CD4+CD25− T cells, in the presence of a polyclonal stimulus, with or without IL-15.

RESULTS:

 

Higher density of CD4+CD25+Foxp3+ T cells was seen in duodenal biopsy samples from active CD patients in comparison with treated CD and non-CD controls. In coculture, CD4+CD25+ T cells were functionally suppressive, but their activity was impaired by IL-15. Cells from CD subjects showed increased sensitivity to the IL-15 action, likely due to enhanced expression of IL-15 receptor. Finally, we demonstrated an expansion of Foxp3 in treated CD mucosa following in vitro challenge with gliadin.

CONCLUSIONS:

 

These data suggest that CD4+CD25+Foxp3+ T cells are induced in situ by gliadin. However, their suppressor capacity might be impaired in vivo by IL-15; this phenomenon contributes to maintain and expand the local inflammatory response in CD.