Size and dynamics of mucosal and peripheral IL-17A+ T-cell pools in pediatric age, and their disturbance in celiac disease

Abstract

Mucosal interleukin (IL)-17A-producing T cells contribute to protective antimicrobial responses and to epithelial barrier integrity; their role in celiac disease (CD) is debated. We analyzed the frequency and developmental dynamics of mucosal (intraepithelial lymphocytes (IEL)) and circulating (peripheral blood (PB)) IL-17A (T17) and/or interferon (IFN)-γ-producing (T1, T1/T17) T-cell populations in 86 pediatric controls and 116 age-matched CD patients upon phorbol myristate acetate/ionomycin or CD3/CD28 stimulation. T17 and T1/17 are physiologically present among IEL and PB populations, and their frequency is selectively and significantly reduced in CD IEL. The physiological age-dependent increase of Th17 IEL is also absent in CD, while IFN-γ-producing PB-T cells significantly accumulate with patient's age. Finally, the amplitude of IL-17A+ and IFN-γ+ T-cell pools are significantly correlated in different individuals; this relationship only applies to CD4+ T cells in controls, while it involves also the CD4- counterpart in CD patients. In conclusion, both size and dynamics of mucosa-associated and circulating IL-17A+ T-cell pools are finely regulated in human pediatric subjects, and severely disturbed in CD. The impaired IL-17A+ IEL-T pool may negatively impact on epithelial barrier efficiency, and contribute to CD mucosa damage; the disturbed dynamics of circulating IL-17A+ and IFN-γ+ T-cell pools may be involved in the extraintestinal autoimmune manifestations associated with CD.

Gluten-sensitive enteropathy coincides with decreased capability of intestinal T cells to secrete IL-17 and IL-22 in a macaque model for celiac disease

“…No association was observed between the IL-17 production and histopathology. It is important to note that latest study measured IL-17A production by T cells that were in vitro stimulated with PMA/ionomycin mitogens — consistent with widely used methodology for intracellular cytokine detection [22]. It appears from these studies that depending on specificity of antigen used for in vitro stimulation, IL-17 production by intestinal T cells from celiac patients can vary [19–22].…”

“…Analogous studies on the roles of IL-17 and IL-22 in celiacs have yielded mixed results [19–22]. In one study, gluten reactive duodenal T cells were obtained from celiac patients after an oral gluten challenge [19].…”

“…In another study that focused on direct detection of gliadin specific Th17 cells in untreated celiac patients, elevated numbers of both IL-17 and IL-22 producing cells were found in small intestinal mucosa [21]. In contrary, another study that focused on intraepithelial lymphocytes found reduced levels of IL-17A secretion in celiac patients on GD in comparison with patients on GFD [22]. No association was observed between the IL-17 production and histopathology.…”

“…While interferon-gamma (IFN-γ) is secreted by celiac T cells [16] and it is capable of activating TG2 via the phosphatidylinosinol-3-kinase pathway [17], IL-17 and IL-22 cytokines are thought to function as innate regulators of mucosal integrity [18]. Impaired but not well-understood kinetics of IL-17/22 cytokine secretion was described in celiac patients [19–22]. In accord with epithelial integrity maintaining function of IL-17 and IL-22, we hypothesized that introduction of dietary gluten to TG2-antibody positive macaques will disrupt capability of intestinal lymphocytes to secrete these cytokines and lead to changes in intestinal tissue architecture.…”

Immunological Approach of the Challenges of the XXI Century in Celiac Disease

“…Surface TCR-CD3 (-) IEL lines isolated from three RCD II patients preferentially lyse epithelial cell lines [11]. The impaired IL-17A+ IEL-T pool may negatively impact on epithelial barrier efficiency, and conduce to CD mucosa damage [12]. In conclusion, mucosal immune cells, especially intraepithelial lymphocytes, are involved in maintaining of the epithelial barriers integrity [13].…”