β7 integrins are required to give rise to intestinal mononuclear phagocytes with tolerogenic potential

Abstract

Background and objective: While pro-inflammatory monocyte trafficking to the intestine has been partially characterised, the molecules required for migration of tolerogenic mononuclear phagocytes (dendritic cells (DC) and macrophages) are unknown. We hypothesised that the gut-homing receptor integrin α4β7 is required for this process.

Methods: We used a T cell-mediated colitis model to study the role of α4β7 in the innate immune compartment. We then performed competitive bone marrow (BM) reconstitution experiments to assess the requirement of α4β7 in the generation of intestinal retinoic acid (RA)-producing CD11c(hi) DC (ALDE(+)DC) and CD64 macrophages. Using mixed BM chimeras we also asked whether α4β7 is required to give rise to tolerogenic mononuclear phagocytes.

Results: Lack of β7 integrins in the innate immune compartment (β7(-/-)RAG2(-/-) mice) markedly accelerated T cell-mediated colitis, which was correlated with lower numbers and frequencies of ALDE(+)DC in mesenteric lymph nodes. Consistent with a role of α4β7 in the generation of intestinal mononuclear phagocytes, BM cells from β7(-/-) mice poorly reconstituted small intestine ALDE(+)DC and Mφ when compared to their wild type counterparts. In addition, mice lacking β7 integrins in the CD11c(hi) compartment showed decreased ability to induce Foxp3(+) T(REG) and IL-10-producing T cells.

Conclusions: Mice lacking β7 integrins in the innate immune compartment are more susceptible to intestinal inflammation, which is correlated with a requirement of β7 integrins to reconstitute gut mononuclear phagocytes with tolerogenic potential.

Keywords: ADHESION MOLECULES; DENDRITIC CELLS; TOLERANCE.