Biology subjects

Agace, W. W.

Publications and source records attributed to Agace, W. W..

6 recordsLinked to original sources

bioRxiv2026

Type 1 and type 2 dendritic cell subsets cooperate to maintain intestinal immune tolerance via integrin αvβ8-mediated TGF-β activation

The gastrointestinal tract is a unique immunological environment where the host must balance tolerance to commensal microbes with defense against pathogens. A critical mechanism for maintaining this balance is the peripheral conversion of naive T cells into regulatory T cells (pTregs), a process that depends on the TGF-{beta} cytokine, which is produced in a latent form and must be activated. While the activation of latent TGF-{beta} relies on the membrane-bound v{beta}8 integrin, the precise cellular subset(s) responsible for this essential process have yet to be clearly defined. Conventional dendritic cells (cDCs), which migrate from the intestinal lamina propria to the gut-draining mesenteric lymph nodes (MLN), have long been considered the primary antigen-presenting cells (APCs) responsible for v{beta}8-mediated TGF-{beta} activation and pTreg induction. However, recent studies have challenged this paradigm by highlighting a new family of rare ROR{gamma}t-expressing APCs, able to induce pTreg via v integrins, raising questions about the in vivo role of cDCs in the maintenance of mucosal immune homeostasis. Using a {beta}8 integrin gene reporter mouse model (Itgb8-IRES-tdTomato) combined with single-cell profiling, we comprehensively mapped Itgb8-expressing APCs in the MLN. We show that cDCs, in particular migratory type 1 (cDC1) and type 2 (cDC2), constitute the predominant Itgb8TdTomato+ cells, both in neonatal and adult mice. Through cDC subset-specific {beta}8 knockout models, we demonstrate that both cDC1 and cDC2 are required for optimal pTreg generation. Loss of {beta}8 integrin in either subset led to a partial reduction in pTreg, while combined deletion resulted in profound pTreg loss and spontaneous colitis. Importantly, these effects were independent of ROR{gamma}t APC populations, including ILC3s and Thetis cells. These findings resolve longstanding questions about the identity of key APCs driving pTreg induction in the MLNs. They demonstrate that cDC1 and cDC2 are non-redundant, essential mediators of pTreg induction and intestinal immune tolerance. Although different populations of ROR{gamma}t APCs may contribute in specific contexts, such as early development, infection, or in the prevention of allergic disease, cDCs remain one of the primary guardians of intestinal immune homeostasis in response to microbiota.

immunology↗

bioRxiv2021

The small and large intestine contain transcriptionally related mesenchymal stromal cell subsets that derive from embryonic Gli1+ mesothelial cells

Intestinal fibroblasts (FB) play essential roles in intestinal homeostasis. Here we show that the small and large intestinal lamina propria (LP) contain similar FB subsets that locate in specific anatomical niches and express distinct arrays of epithelial support genes. However, there were tissue specific differences in the transcriptional profile of intestinal FB subsets in the two sites. All adult intestinal LP mesenchymal stromal cells (MSC), including FB, smooth muscle cells (SMC) and pericytes derive from Gli1-expressing embryonic precursors which we identify as mesothelial cells. Trajectory analysis suggested that adult SMC and FB derive from distinct embryonic intermediates, and that adult FB subsets develop in a linear trajectory from CD81+ FB. Finally, we show that colonic subepithelial PDGFRhi FB comprise several functionally and anatomically distinct populations that originate from an Fgfr2-expressing FB intermediate. Collectively our results provide novel insights into MSC diversity, location, function and ontogeny, with implications for our understanding of intestinal development, homeostasis and disease.

developmental biology↗

bioRxiv2021

Single-cell characterisation of mononuclear phagocytes in the human intestinal mucosa

Mononuclear phagocytes (MNP), including macrophages and classical dendritic cells (cDC), are highly heterogeneous cells with distinct functions. Understanding MNP complexity in the intestinal lamina propria (LP), particularly in humans, has proved difficult due to the expression of overlapping phenotypic markers and the inability to isolate these cells without contamination from gut-associated lymphoid tissues (GALT). Here, we exploited our novel method for isolation of human GALT-free LP to carry out single-cell (sc)RNA-seq, CITE-seq and flow cytometry analysis of human ileal and colonic LP MNPs. As well as classical monocytes, non-classical monocytes, mature macrophage subsets, cDC1s, and cDC2s, we identified a CD1c+ cDC subset with features of both cDC2 and monocytes, which were transcriptionally similar to the recently described cDC3. While similar MNP subsets were present in both ileal and colonic LP, the proportions and transcriptional profiles of these populations differed between these sites and in diseased states, indicating local specialization and environmental imprinting. Using computational trajectory tools, we identified putative early committed pre-cDC subsets and developmental intermediates of mature cDC1, cDC2 and cDC3, as well as monocyte-to-macrophage trajectories. Collectively, our results provide novel insights into the heterogeneity and development of intestinal LP MNP and an important framework for studying the role of these populations in intestinal homeostasis and disease. One sentence summaryFenton and Wulff et al. use single-cell methods to explore the complexity of the mononuclear phagocyte compartment of the human intestinal lamina propria, identifying distinct dendritic cell and macrophage subsets, site-specific transcriptional signatures, and lineage-specific precursors.

immunology↗

bioRxiv2019

Lysates of Methylococcus capsulatus Bath induce a lean-like microbiota, intestinal FoxP3+RORγt+IL-17+ Tregs and improve metabolism

Interactions between host and gut microbial communities may be modulated by diets and play pivotal roles in securing immunological homeostasis and health. Here we show that intake of feed based on whole-cell lysates of the non-commensal bacterium Methylococcus capsulatus Bath (McB) as protein source reversed high fat high sucrose-induced changes in the gut microbiota to a state resembling that of lean, low fat diet-fed mice, both under mild thermal stress (T22{degrees}C) and at thermoneutrality (T30{degrees}C). McB feeding selectively upregulated triple positive (Foxp3+ROR{gamma}t+IL-17+) regulatory T cells in the small intestine and colon, and enhanced mucus production and glycosylation status suggesting improved gut health. Mice receiving McB lysates further exhibited improved glucose regulation, reduced body and liver fat along with diminished hepatic immune infiltration. Collectively, these data points towards profound whole-body effects elicited by the McB lysate suggesting that it may serve as a potent modulator of immunometabolic homeostasis.

immunology↗

bioRxiv2019

Migration of intestinal dendritic cell subsets upon intrinsic and extrinsic TLR3 stimulation

Initiation of adaptive immunity to particulate antigens in lymph nodes largely depends on their presentation by migratory dendritic cells (DCs). DC subsets differ in their capacity to induce specific types of immunity, allowing subset-specific DC-targeting to influence vaccination and therapy outcomes. Faithful drug design however requires exact understanding of subset-specific versus global activation mechanisms. cDC1, the subset of DCs that excel in supporting immunity towards viruses, intracellular bacteria and tumors, express uniquely high levels of the pattern recognition receptor TLR3. Using various genetic models, we show here that both the cDC1 and cDC2 subsets of cDCs are activated and migrate equally well in response to TLR3 stimulation in a cell extrinsic and TNF dependent manner, but that cDC1 show a unique requirement for type I interferon signaling. Our findings reveal common and differing pathways regulating DC subset migration, offering important insights for the design of DC-based vaccination and therapy approaches.

immunology↗

bioRxiv2018

Bow-tie motifs enable protein multifunctionality by connecting cellular processes in the interactome

Abstract (172/175 words)Cell type-specific protein interactomes are promising resources for the understanding of cell functionality and genetic perturbations in cellular states. However, while many low-and top-level aspects of interactome topology have been mapped, we still lack an understanding of the topological motifs at the intermediate level, where connectivity between cellular processes takes place. We combine conventional dendritic cell lineage 1 (cDC1)-specific expression data with a high-quality protein interactome, subsequently creating an information-rich cDC1-specifc interactome matrix that displays topological information on an unprecedented 36.7 million protein pairs at once. By dissecting the interactome-matrix, we reveal that the bow-tie motif is a major connector of cellular processes and an extremely widespread topology in the protein interactome. In aggregation, the bow-tie motifs form a scaffold within the interactome that hierarchically link cellular processes together. We further demonstrate that the bow-tie motifs design can enable protein multifunction. Our generic approach allows a topological characterization and visualization of any large network, facilitating a more effective usage of community-produced interaction data, and is applicable to any cell types interactome.

systems biology↗