No abstract

The intestine is constantly exposed to foreign antigens, which are mostly innocuous but can sometimes be harmful. Therefore, the intestinal immune system has the delicate task of maintaining immune tolerance to harmless food antigens while inducing tailored immune responses to pathogens and regulating but tolerating the microbiota. Intestinal dendritic cells (DCs) play a central role in these functions as sentinel cells able to prime and polarize the T cell responses. DCs are deployed throughout the intestinal mucosa but with local specializations along the gut length and between the diffuse effector sites of the gut lamina propria (LP) and the wellorganized immune inductive sites comprising isolated lymphoid follicles (ILFs), Peyer's patches (PPs), and other species-specific gutassociated lymphoid tissues (GALTs). Understanding the specificities of each intestinal DC subset, how environmental factors influence DC functions, and how these can be modulated is key to harnessing the therapeutic potential of mucosal adaptive immune responses, whether by enhancing the efficacy of mucosal vaccines or by increasing tolerogenic responses in inflammatory disorders. In this review, we summarize recent findings related to intestinal DCs in steady state and upon inflammation, with a special focus on their functional specializations, highly dependent on their microenvironment.

Microbiome research is hampered by the fact that many bacteria are still unknown and by the lack of publicly available isolates. Fundamental and clinical research is in need of comprehensive and well-curated repositories of cultured bacteria from the intestine of mammalian hosts. In this work, we expanded the mouse intestinal bacterial collection (www.dsmz.de/miBC) to 212 strains, all publicly available and taxonomically described. This includes the study of strain-level diversity, small-sized bacteria, and the isolation and characterization of the first cultured members of one novel family, 10 novel genera, and 39 novel species. We demonstrate the value of this collection by performing two studies. First, metagenome-educated design of synthetic communities (SYNs) allowed establishing custom strain consortia that reflect different susceptibilities to DSS-induced colitis. Second, nine phylogenetically and functionally diverse species were used to amend the Oligo-Mouse Microbiota (OMM)12 model [Brugiroux et al. 2016 Nat Microbiol]. These strains compensated for differences observed between gnotobiotic OMM12 and specific-pathogen free (SPF) mice at multiple levels, including body composition and immune cell populations (e.g., induction of T-cell subtypes) in the intestine and associated lymphoid tissues. Ready-to-use OMM stocks from this work are available to the community for use in future studies. In conclusion, this work improves our knowledge of gut microbiota diversity in mice and enables functional studies via the modular use of isolates.

Macrophages are traditionally considered antigen-presenting cells. However, their ability to present antigen and the factors regulating macrophage MHCII expression are poorly understood. Here, we demonstrate that MHCII expression on murine intestinal macrophages is differentially controlled by their residence in the small intestine (SI) or the colon, their ontogeny and the gut microbiota. Monocyte-derived macrophages are uniformly MHCIIhi, independently of the tissue of residence, microbial status or the age of the mouse, suggesting a common monocyte differentiation pathway. In contrast, MHCII expression on long-lived, prenatally-derived Tim4+ macrophages is low after birth but significantly increases at weaning in both SI and colon. Furthermore, MHCII expression on colonic Tim4+, but not monocyte-derived macrophages, is dependent on recognition of microbial stimuli, as MHCII expression is significantly downregulated in germ-free, antibiotic-treated and MyD88 deficient mice. To address the function of MHCII presentation by intestinal macrophages we established two models of macrophage-specific MHCII deficiency. We observed a significant reduction in the overall frequency and number of tissue-resident, but not newly arrived, SI CD4+ T cells in the absence of macrophage-expressed MHCII. Our data suggest that macrophage MHCII provides signals regulating gut CD4+ T cell maintenance with different requirements in the SI and colon.