Intestinal macrophages play a vital role in controlling the balance of immunity and tolerance. Much is known about their ability to regulate both tolerogenic and inflammatory T cell responses by the production of a variety of cytokines, both in the small intestine (SI) and colon. Traditionally, macrophages have been considered antigen-presenting cells (APCs), based on their expression of the antigen presenting molecule MHC-II. However, little is known about the capacity of intestinal

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... to present antigen and stimulate CD4 T cell responses locally. Furthermore, it is unclear which molecular mechanisms and environmental factors regulate the high expression of MHC-II on the surface of intestinal macrophages. In this study, we demonstrate that MHC-II expression on macrophages depends both on their ontogeny and tissue of residence. Monocyte-derived tissue macrophages almost exclusively had high levels of surface MHC-II, regardless of the tissue of residence. Interestingly, amongst different prenatally derived tissue macrophages, both SI and colonic Tim4+ macrophages in mice were the highest MHC-II-expressing populations. In the SI, all macrophages were uniformly high in their MHC-II expression. However, in the colon, a substantial population of prenatally derived Tim4+ macrophages expressed low levels of surface MHC-II. Furthermore, MHC-II expression on mouse SI and colonic macrophages exhibited different kinetics during neonatal development and in particular around weaning. Since colonic macrophages are in close contact with the gut microbiota, we hypothesised that this interaction may play a major role in regulating their MHC-II expression. In accordance with this, we observed lower frequencies of MHC-IIhigh and an increase in MHC-IIlow macrophages in the colon, but not in the small intestine of germ-free (GF) or antibiotics-treated (ABX) mice. Notably, in both cases, the MHC-IIlow colonic macrophages were Tim4 positive, suggesting that the microbiota specifically regulates MHC-II expression on prenatally- [...]