IL-15 controls T cell functions through its influence on CD30 and OX40 antigens in Celiac Disease

• We demonstrate a distinct new function of IL-15 in Celiac Disease.
• IL-15 induces OX40+ T cells with a regulatory phenotype in Celiac Disease.
• CD3+CD30+ IFN-γ+ T blasts contribute to the type I response in Celiac Disease.

AimTo evaluate the ability of interleukin (IL)-15 to control T cell functions through its influence on CD30 and OX40 expressing cells in Celiac Disease (CD). In peripheral blood (PB), by examining the expression of OX40 in conventional effectors cells and T cells with a phenotypic specialization of regulatory cells [CD4+CD25high forkhead box protein 3 (Foxp3)+], and the co stimulation of IFN-γ and IL-4 production within CD30 and OX40 positive subsets of T cells. At the duodenal mucosa, by assessing the expression of CD30 and OX40 in intraepithelial (IE) and lamina propria (LP) lymphocytes (IEL, LPL).Patients and methodsPB and duodenal mucosal biopsies were obtained from 38 patients with classic CD (Cel) and 38 healthy controls (HC). Analysis of cell surface and/or intracellular antigens was performed in anti-CD3-treated PB mononuclear cells (PBMC) before and after treatment with recombinant IL-15 (rIL-15), and in IE and LP cellular suspensions prepared from duodenal biopsies pre-treated with/without rIL-15.ResultsA subpopulation of CD3+OX40+ T blasts was induced in Cel and HC by a 3 days treatment of PBMC with anti-CD3 and decreased its size thereafter, regardless of the presence of rIL-15. However, the addition of rIL-15 to T blasts distinctively induced the survival of T cells with a regulatory phenotype that expresses OX40 antigen in Cel (p < 0.05). Celiac patients showed higher frequencies of IFN-γ-producing CD3+CD30+ blasts before and after treatment with rIL-15 (p < 0.05, vs. HC). IL-15 increased the frequencies of CD3+CD30+ LPL (HC: p < 0.05, Cel: p < 0.05) but not of CD3+OX40+ LPL, and CD30 or OX40 positive IEL.ConclusionsThe distinctive control of OX40+ cells with a T regulatory phenotype mediated by the influence of IL-15 comes out as new function of this cytokine in the context of CD. The higher production of IFN-γ by a subpopulation of peripheral CD3+CD30+ cells contributes to the type I biased immune response.