Macrophage-mediated gliadin degradation and concomitant IL-27 production drive IL-10- and IFN-[gamma]-secreting Tr1-like-cell differentiation in a murine model for gluten tolerance

• Published in: Mucosal immunology Vol. 10; no. 3; p. 635
• Main Authors: Van Leeuwen, M A, Costes, L M M, Van Berkel, L A, Simons-oosterhuis, Y, Du Pré, M F, Kozijn, A E, Raatgeep, H C, Lindenbergh-kortleve, D J, Van Rooijen, N, Koning, F, Samsom, J N
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 01.05.2017
• ISSN: 1933-0219; 1935-3456
• DOI: 10.1038/mi.2016.76

Celiac disease is caused by inflammatory T-cell responses against the insoluble dietary protein gliadin. We have shown that, in humanized mice, oral tolerance to deamidated chymotrypsin-digested gliadin (CT-TG2-gliadin) is driven by tolerogenic interferon (IFN)-γ- and interleukin (IL)-10-secreting type 1 regulatory T-like cells (Tr1-like cells) generated in the spleen but not in the mesenteric lymph nodes. We aimed to uncover the mechanisms underlying gliadin-specific Tr1-like-cell differentiation and hypothesized that proteolytic gliadin degradation by splenic macrophages is a decisive step in this process. In vivo depletion of macrophages caused reduced differentiation of splenic IFN-γ- and IL-10-producing Tr1-like cells after CT-TG2-gliadin but not gliadin peptide feed. Splenic macrophages, rather than dendritic cells, constitutively expressed increased mRNA levels of the endopeptidase Cathepsin D; macrophage depletion significantly reduced splenic Cathepsin D expression in vivo and Cathepsin D efficiently degraded recombinant γ-gliadin in vitro. In response to CT-TG2-gliadin uptake, macrophages enhanced the expression of Il27p28, a cytokine that favored differentiation of gliadin-specific Tr1-like cells in vitro, and was previously reported to increase Cathepsin D activity. Conversely, IL-27 neutralization in vivo inhibited splenic IFN-γ- and IL-10-secreting Tr1-like-cell differentiation after CT-TG2-gliadin feed. Our data infer that endopeptidase mediated gliadin degradation by macrophages and concomitant IL-27 production drive differentiation of splenic gliadin-specific Tr1-like cells.