title: IL-15 interferes with suppressive activity of intestinal regulatory T cells expanded in Celiac disease.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Paediatrics University Federico II, Naples, Italy. gmazzarella@isa.cnr.it
authors.forename: Delia
authors.initials: D
authors.lastname: Zanzi
authors.forename: Rosita
authors.initials: R
authors.lastname: Stefanile
authors.forename: Sara
authors.initials: S
authors.lastname: Santagata
authors.forename: Laura
authors.initials: L
authors.lastname: Iaffaldano
authors.forename: Gaetano
authors.initials: G
authors.lastname: Iaquinto
authors.forename: Nicola
authors.initials: N
authors.lastname: Giardullo
authors.forename: Giuliana
authors.initials: G
authors.lastname: Lania
authors.forename: Ilaria
authors.initials: I
authors.lastname: Vigliano
authors.forename: Aufiero Rotondi
authors.initials: AR
authors.lastname: Vera
authors.forename: Katia
authors.initials: K
authors.lastname: Ferrara
authors.forename: Salvatore
authors.initials: S
authors.lastname: Auricchio
authors.forename: Riccardo
authors.initials: R
authors.lastname: Troncone
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Mazzarella
mesh_terms: D000293:Adolescent; D000328:Adult; D017252:CD3 Complex / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D002446:Celiac Disease / Q000188:drug therapy / Q000378:metabolism*; D002478:Cells, Cultured; D004386:Duodenum / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005903:Gliadin / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000378:metabolism; D019409:Interleukin-15 / Q000494:pharmacology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D055815:Young Adult
chemical_list: D017252:CD3 Complex; D015704:CD4 Antigens; D016827:CD8 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D019409:Interleukin-15; D053645:Interleukin-2 Receptor alpha Subunit; D007371:Interferon-gamma; D005903:Gliadin