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Intestinal T Cell Responses to Gluten Peptides Are Largely Heterogeneous: Implications for a Peptide-Based Therapy in Celiac Disease¹

Alessandra Camarca^*, Robert P. Anderson, Gianfranco Mamone^*, Olga Fierro^*, Angelo Facchiano^*, Susan Costantini^*, Delia Zanzi, John Sidney, Salvatore Auricchio, Alessandro Sette, Riccardo Troncone and Carmen Gianfrani^2,*

^* Institute of Food Sciences-National Research Council, Avellino, Italy; Autoimmunity and Transplantation Division, Walter and Eliza Hall Institute, Parkville, Victoria, Australia; Department of Paediatrics and European Laboratory for the Investigation of Food-Induced Diseases, University of Naples, Federico II, Naples, Italy; and La Jolla Institute for Allergy and Immunology, San Diego, CA 92121

The identification of gluten peptides eliciting intestinal T cell responses is crucial for the design of a peptide-based immunotherapy in celiac disease (CD). To date, several gluten peptides have been identified to be active in CD. In the present study, we investigated the recognition profile of gluten immunogenic peptides in adult HLA-DQ2⁺ celiac patients. Polyclonal, gliadin-reactive T cell lines were generated from jejunal mucosa and assayed for both proliferation and IFN- production in response to 21 peptides from wheat glutenins and -, -, and -gliadins. A magnitude analysis of the IFN- responses was performed to assess the hierarchy of peptide potency. Remarkably, 12 of the 14 patients recognized a different array of peptides. All -gliadin stimulatory peptides mapped the 57–89 N-terminal region, thus confirming the relevance of the known polyepitope 33-mer, although it was recognized by only 50% of the patients. By contrast, -gliadin peptides were collectively recognized by the great majority (11 of 14, 78%) of CD volunteers. A 17-mer variant of 33-mer, QLQPFPQPQLPYPQPQP, containing only one copy of DQ2--I and DQ2--II epitopes, was as potent as 33-mer in stimulating intestinal T cell responses. A peptide from -gliadin, QPQQPFPQPQQPFPWQP, although structurally related to the -gliadin 17-mer, is a distinct epitope and was active in 5 out of 14 patients. In conclusion, these results showed that there is a substantial heterogeneity in intestinal T cell responses to gluten and highlighted the relevance of - and -gliadin peptides for CD pathogenesis. Our findings indicated that -gliadin (57–73), -gliadin (139–153), and -gliadin (102–118) are the most active gluten peptides in DQ2⁺ celiac patients.

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 Supported by Regione Campania Grant POR RT05B.

² 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

³ Abbreviations used in this paper: CD, celiac disease; B-LCL, EBV-lymphoblastoid cell line; iTCL, intestinal T cell line; PT, peptic-tryptic; TCC, T cell clone; TG2, tissue transglutaminase.