The intestinal expansion of TCRγδ⁺ and disappearance of IL4⁺ T cells suggest their involvement in the evolution from potential to overt celiac disease

Abstract

Celiac disease (CD) is characterized by a spectrum of intestinal inflammatory lesions.Most patients have villous atrophy (overt-CD), while others have a morphologically normal mucosa, despite the presence of CD-specific autoantibodies (potential-CD). As the mechanism responsible for villous atrophy is not completely elucidated, we investigated biomarkers specific for the different celiac lesions. Phenotype and cytokine production of intestinal mucosa cells were analyzed by flow cytometry in gut biopsies of children with overt-or potential-CD and in healthy controls. Density of TCRγδ + T cells was found markedly enhanced in intestinal mucosa of children with overt-CD compared to potential-CD or controls. By contrast, very few IL4 + T cells infiltrated the mucosa with villous atrophy compared to morphologically normal mucosa. IL4 + T cells were classical CD4 + T-helper cells (CD161 − ), producing or not IFN-γ, and negative for IL17A. Our study demonstrated that the transition to villous atrophy in CD patients is characterized by increased density of TCRγδ + T cells, and concomitant disappearance of IL4 + cells. These findings suggest that immunomodulatory mechanisms are active in potential-CD to counteract the inflammatory cascade responsible of villous atrophy. Further studies are required to validate the use of IL4 + and TCRγδ + T cells as biomarkers of the different CD forms.Keywords: Celiac disease r Cytokines r Flow cytometry r Intestinal TCRγδ + T cells r Mucosal immunology Additional supporting information may be found online in the Supporting Information section at the end of the article.

Characterization of the “gut microbiota-immunity axis” and microbial lipid metabolites in atrophic and potential celiac disease

“…Moreover, in accordance with Vitale et al, pCD patients showed a high percentage of T cells co-producing IL-17, IL-4, and IFN-γ (Th0/Th17 p < 0.00005, Tc0/Tc17; Vitale et al, 2019). Notably, IL-17 is a pro-inflammatory cytokine, but a number of studies underlined its potential involvement in the prevention of gut mucosa inflammation (Mucida and Salek-Ardakani, 2009;Cukrowska et al, 2017).…”

Intestinal Cellular Biomarkers of Mucosal Lesion Progression in Pediatric Celiac Disease

“…In this follow-up study, in order to corroborate previous findings [17], we investigated these two lymphocyte populations in a larger number of pediatric subjects including patients with overt-CD, potential-CD and an age-matched control group of non-celiac subjects (henceforth identified as controls). In particular, we investigated the frequency of TCRγδ+ and IL4+ intestinal T lymphocytes by a multiparametric flow cytometry analysis on both intestinal cells freshly isolated from the mucosal samples and short-term T-cell lines (st-TCLs).…”

“…Recently, we reported that the transition from a histologically normal intestinal mucosa of potential-celiacs to villous atrophy of overt-celiacs is associated with a marked intestinal expansion of TCRγδ+ T cells and a concomitant disappearance of IL4-producing T cells, likely CD4+ Th2 cells [17]. These preliminary findings strongly suggested that changes in the frequencies of these T cell populations in gut mucosa could influence the progression from mild towards severe mucosal inflammation and tissue damage.…”

“…Nevertheless, the specific inflammatory pathways responsible for the progression of the intestinal lesion from mild to severe, as well as the regulatory mechanisms that contrast this transition from potential-CD to overt-CD, have not yet been clearly defined. We recently showed that in pediatric CD patients the intestinal mucosa with villous atrophy is characterized by an expansion of TCRγδ+ IELs and a concomitant disappearance of IL4-producing CD4+ T cells, if compared to the morphologically normal mucosa of potential-CD patients in which IL4+ cells were markedly present [17]. These IL4+ T cells showed two different cytokine profiles, as they co-produced or not INFγ and IL17, suggesting the presence of IL4+ cells with a Th2 phenotype.…”

“…Our recent study [17] suggested that TCRγδ+ and IL4+ T cells could be cellular biomarkers of the evolution of mucosal lesion in CD. The identification of specific biomarkers, predicting the aggravation of tissue damage in subjects at the early stages of intestinal inflammation, could make it possible to discriminate, among the potential-CD patients, those at high-risk to develop the villous atrophy when on a gluten-containing diet.…”