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Gliadin-Specific Type 1 Regulatory T Cells from the Intestinal Mucosa of Treated Celiac Patients Inhibit Pathogenic T Cells

Carmen Gianfrani^1,*, Megan K. Levings^2,,, Claudia Sartirana, Giuseppe Mazzarella^*, Gianvincenzo Barba^*, Delia Zanzi, Alessandra Camarca^*,, Gaetano Iaquinto, Nicola Giardullo, Salvatore Auricchio, Riccardo Troncone^*, and Maria-Grazia Roncarolo^,¶

^* Institute of Food Science-Consiglio Nazionale delle Ricerche, Avellino, Italy; San Raffaele Telethon Institute for Gene Therapy (Hospital San Raffaele-Telethon Institute for Gene Therapy). Milan, Italy; Department of Pediatrics and European Laboratory for the Investigation of Food-Induced Diseases, University Federico II, Naples, Italy; Gastroenterology Unit, Moscati Hospital, Avellino, Italy; and ^¶ Vita-Salute San Raffaele University, Milan, Italy

Celiac disease (CD) results from a permanent intolerance to dietary gluten and is due to a massive T cell-mediated immune response to gliadin, the main component of gluten. In this disease, the regulation of immune responses to dietary gliadin is altered. Herein, we investigated whether IL-10 could modulate anti-gliadin immune responses and whether gliadin-specific type 1 regulatory T (Tr1) cells could be isolated from the intestinal mucosa of CD patients in remission. Short-term T cell lines were generated from jejunal biopsies, either freshly processed or cultured ex vivo with gliadin in the presence or absence of IL-10. Ex vivo stimulation of CD biopsies with gliadin in the presence of IL-10 resulted in suppression of Ag-specific proliferation and cytokine production, indicating that pathogenic T cells are susceptible to IL-10-mediated immune regulation. T cell clones generated from intestinal T cell lines were tested for gliadin specificity by cytokine production and proliferative responses. The majority of gliadin-specific T cell clones had a Th0 cytokine production profile with secretion of IL-2, IL-4, IFN-, and IL-10 and proliferated in response to gliadin. Tr1 cell clones were also isolated. These Tr1 cells were anergic, restricted by DQ2 (a CD-associated HLA), and produced IL-10 and IFN-, but little or no IL-2 or IL-4 upon activation with gliadin or polyclonal stimuli. Importantly, gliadin-specific Tr1 cell clones suppressed proliferation of pathogenic Th0 cells. In conclusion, dietary Ag-specific Tr1 cells are present in the human intestinal mucosa, and strategies to boost their numbers and/or function may offer new therapeutic opportunities to restore gut homeostasis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Carmen Gianfrani, Istituto di Scienze dell’Alimentazione-Consiglio Nazionale delle Ricerche, Via Roma 52A/C, 83100, Avellino, Italy. E-mail address: cgianfrani{at}isa.cnr.it

² Current address: Department of Surgery, University of British Columbia, Vancouver, B.C.

³ Abbreviations used in this paper: CD, celiac disease; Tr1, type 1 regulatory T cell; IBD, inflammatory bowel disease; TCL, T cell line; TCC, T cell clone; SI, stimulation index; LCL, lymphoblastoid cell line; ctl, control.