Characterization of Gliadin-Specific Th17 Cells from the Mucosa of Celiac Disease Patients

OBJECTIVES: Celiac disease (CD) is a disorder characterized by a deregulated immune response to ingested wheat gluten and related cereal proteins in susceptible individuals. It has been considered that the onset of CD is mediated by a skewed Th1 response. However, the participation of Th17 cells in the pathogenesis of the disease, a key cell population in other autoimmune disorders, has not been studied in detail. We have investigated the presence of Th17 cells in the mucosa of active CD patients and their functional implications in the pathogenesis of the disease. METHODS: T cells obtained from duodenum biopsies from 15 untreated patients and 11 control individuals were characterized by flow cytometry, immunoassays, and real-time PCR. RESULTS: We found gliadin-specific CD4(+) interleukin (IL)-17A-producing T cells in the mucosa of CD patients with a phenotype consisting of TCR (T-cell receptor)alpha beta(+) CD45RO(+) CD161(+) CCR6(+) (C-C chemokine receptor type 6) and IL-23R(+). Functional analysis showed that Th17 cells from CD patients are different from those of control individuals in terms of cytokines production. Th17 cells from CD patients, but not from controls, simultaneously express transforming growth factor-beta (TGF beta). Th17 CD cells also produce interferon-gamma (IFN gamma), IL-21, and IL-22. The analysis of the transcription factors revealed a high expression of interferon regulatory factor-4 as a feature of gliadin-specific cells from CD patients with respect to controls. CONCLUSIONS: Gliadin-specific Th17 cells are present in the mucosa of CD patients having a dual role in the pathogenesis of the disease as they produce proinflammatory cytokines (such as IL-17, IFN gamma, IL-21), mucosa-protective IL-22, and regulatory TGF beta, which actively modulates IL-17A production by T cells in the celiac mucosa.