Macrophage-mediated gliadin degradation and concomitant IL-27 production drive IL-10- and IFN-γ 3-secreting Tr1-like-cell differentiation in a murine model for gluten tolerance

M. A. Van Leeuwen, L. M.M. Costes, L. A. Van Berkel, Y. Simons-Oosterhuis, M. F. Du Pré, A. E. Kozijn, H. C. Raatgeep, D. J. Lindenbergh-Kortleve, N. Van Rooijen, F. Koning, J. N. Samsom*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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 3- 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 3- 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 3-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 3- 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.

Original languageEnglish
Pages (from-to)635-649
Number of pages15
JournalMucosal Immunology
Issue number3
Publication statusPublished - 1 May 2017

Cite this