Search

Oral tolerance is the process by which feeding of soluble proteins induces antigen-specific systemic immune unresponsiveness. Oral tolerance is thought to have a central role in suppressing immune responses to 'harmless' food antigens, and its failure can lead to development of pathologies such as food allergies or coeliac disease. However, on the basis of long-standing experimental observations, the relevance of oral tolerance in human health has achieved new prominence recently following the discovery that oral administration of peanut proteins prevents the development of peanut allergy in at-risk human infants. In this Review, we summarize the new mechanistic insights into three key processes necessary for the induction of tolerance to oral antigens: antigen uptake and transport across the small intestinal epithelial barrier to the underlying immune cells; the processing, transport and presentation of fed antigen by different populations of antigen-presenting cells; and the development of immunosuppressive T cell populations that mediate antigen-specific tolerance. In addition, we consider how related but distinct processes maintain tolerance to bacterial antigens in the large intestine. Finally, we outline the molecular mechanisms and functional consequences of failure of oral tolerance and how these may be modulated to enhance clinical outcomes and prevent disease., (© 2024. Springer Nature Limited.)

The intestinal lamina propria contains a diverse network of fibroblasts that provide key support functions to cells within their local environment. Despite this, our understanding of the diversity, location and ontogeny of fibroblasts within and along the length of the intestine remains incomplete. Here we show that the small and large intestinal lamina propria contain similar fibroblast subsets that locate in specific anatomical niches. Nevertheless, we find that the transcriptional profile of similar fibroblast subsets differs markedly between the small intestine and colon suggesting region specific functions. We perform in vivo transplantation and lineage-tracing experiments to demonstrate that adult intestinal fibroblast subsets, smooth muscle cells and pericytes derive from Gli1-expressing precursors present in embryonic day 12.5 intestine. Trajectory analysis of single cell RNA-seq datasets of E12.5 and adult mesenchymal cells suggest that adult smooth muscle cells and fibroblasts derive from distinct embryonic intermediates and that adult fibroblast subsets develop in a linear trajectory from CD81 + fibroblasts. Finally, we provide evidence that colonic subepithelial PDGFRα hi fibroblasts comprise several functionally distinct populations that originate from an Fgfr2-expressing fibroblast intermediate. Our results provide insights into intestinal stromal cell diversity, location, function, and ontogeny, with implications for intestinal development and homeostasis., (© 2023. The Author(s).)

For many years, the intestine was one of the poor relations of the immunology world, being a realm inhabited mostly by specialists and those interested in unusual phenomena. However, this has changed dramatically in recent years with the realization of how important the microbiota is in shaping immune function throughout the body, and almost every major immunology institution now includes the intestine as an area of interest. One of the most important aspects of the intestinal immune system is how it discriminates carefully between harmless and harmful antigens, in particular, its ability to generate active tolerance to materials such as commensal bacteria and food proteins. This phenomenon has been recognized for more than 100 years, and it is essential for preventing inflammatory disease in the intestine, but its basis remains enigmatic. Here, I discuss the progress that has been made in understanding oral tolerance during my 40 years in the field and highlight the topics that will be the focus of future research.

CD103 + CD11b + dendritic cells (DCs) are unique to the intestine, but the factors governing their differentiation are unclear. Here we show that transforming growth factor receptor 1 (TGFβR1) has an indispensable, cell intrinsic role in the development of these cells. Deletion of Tgfbr1 results in markedly fewer intestinal CD103 + CD11b + DCs and a reciprocal increase in the CD103 - CD11b + dendritic cell subset. Transcriptional profiling identifies markers that define the CD103 + CD11b + DC lineage, including CD101, TREM1 and Siglec-F, and shows that the absence of CD103 + CD11b + DCs in CD11c-Cre.Tgfbr1 fl/fl mice reflects defective differentiation from CD103 - CD11b + intermediaries, rather than an isolated loss of CD103 expression. The defect in CD103 + CD11b + DCs is accompanied by reduced generation of antigen-specific, inducible FoxP3 + regulatory T cells in vitro and in vivo, and by reduced numbers of endogenous Th17 cells in the intestinal mucosa. Thus, TGFβR1-mediated signalling may explain the tissue-specific development of these unique DCs.Developmental cues for the different dendritic cell (DC) subsets in the intestine are yet to be defined. Here the authors show that TGFβR1 signalling is needed for development of CD103 + CD11b + intestinal DCs from CD103 - CD11b + cells and that they contribute to the generation of Th17 and regulatory T cells.

Peritoneal macrophages are one of the most studied macrophage populations in the body, yet the composition, developmental origin and mechanisms governing the maintenance of this compartment are controversial. Here we show resident F4/80(hi)GATA6(+) macrophages are long-lived, undergo non-stochastic self-renewal and retain cells of embryonic origin for at least 4 months in mice. However, Ly6C(+) monocytes constitutively enter the peritoneal cavity in a CCR2-dependent manner, where they mature into short-lived F4/80(lo)MHCII(+) cells that act, in part, as precursors of F4/80(hi)GATA6(+) macrophages. Notably, monocyte-derived F4/80(hi) macrophages eventually displace the embryonic population with age in a process that is highly gender dependent and not due to proliferative exhaustion of the incumbent embryonic population, despite the greater proliferative activity of newly recruited cells. Furthermore, although monocyte-derived cells acquire key characteristics of the embryonic population, expression of Tim4 was impaired, leading to cumulative changes in the population with age.

The intestine represents the largest compartment of the immune system. It is continually exposed to antigens and immunomodulatory agents from the diet and the commensal microbiota, and it is the port of entry for many clinically important pathogens. Intestinal immune processes are also increasingly implicated in controlling disease development elsewhere in the body. In this Review, we detail the anatomical and physiological distinctions that are observed in the small and large intestines, and we suggest how these may account for the diversity in the immune apparatus that is seen throughout the intestine. We describe how the distribution of innate, adaptive and innate-like immune cells varies in different segments of the intestine and discuss the environmental factors that may influence this. Finally, we consider the implications of regional immune specialization for inflammatory disease in the intestine.

The intestinal immune system has to discriminate between harmful and beneficial antigens. Although strong protective immunity is essential to prevent invasion by pathogens, equivalent responses against dietary proteins or commensal bacteria can lead to chronic disease. These responses are normally prevented by a complex interplay of regulatory mechanisms. This article reviews the unique aspects of the local microenvironment of the intestinal immune system and discuss how these promote the development of regulatory responses that ensure the maintenance of homeostasis in the gut.