Microbiota-Dependent Crosstalk Between Macrophages and ILC3 Promotes Intestinal Homeostasis

By A. Mortha, A. Chudnovskiy, D. Hashimoto, M. Bogunovic, S. Spencer, Y. Belkaid, Miriam Merad. Science, 2014

785 citations recorded by the source corpus.

Introduction The gastrointestinal tract is colonized by an extraordinarily large number of commensal microbes and is constantly exposed to ingested antigens and potential pathogens. Regulation of intestinal tolerance thus represents the main task of the immune system of the gut mucosa. Accumulated evidence suggests that gut commensals contribute to the maintenance of intestinal homeostasis, partly through their ability to control the differentiation of effector T lymphocytes in the mucosa and to modulate inflammatory responses through the induction of regulatory T cells (Tregs) and interleukin-10 (IL-10) production. Tissue-resident mononuclear phagocytes (MNPs), including macrophages (MPs) and dendritic cells (DCs), are specifically equipped to detect a wide range of microbial signals and to capture, process, and present extracellular antigenic material to T lymphocytes. MNPs have been shown to contribute to the maintenance of intestinal immune tolerance through the induction or expansion of Tregs in the intestine. Despite their key role in microbial sensing and immune tolerance, the cellular and molecular cues that translate microbial signals into immunoregulatory MNPs in the intestine are not completely understood. ILC3 translate microbial cues into immunoregulatory signals in the intestine. Microbial cues sensed by intestinal MPs lead to IL-1β release. IL-1β engages IL-1R on ILC3, promoting Csf2 release. ILC3-derived Csf2 triggers DC and MP production of regulatory molecules (i.e., RA and IL-10), which, in turn, promotes the induction and expansion of regulatory T cells. Csf2-primed DCs and MPs promote Treg homeostasis locally and in mesenteric lymph nodes. ILC3 translate microbial cues into immunoregulatory signals in the intestine. Microbial cues sensed by intestinal MPs lead to IL-1β release. IL-1β engages IL-1R on ILC3, promoting Csf2 release. ILC3-derived Csf2 triggers DC and MP production of regulatory molecules (i.e., RA and IL-10), which, in turn, promotes the induction and expansion of regulatory T cells. Csf2-primed DCs and MPs promote Treg homeostasis locally and in mesenteric lymph nodes. Rationale The cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF), recently renamed Csf2, is a key determinant of myeloid lineage differentiation and is required for the optimal function of tissue MNPs. Recent results from our laboratory revealed that although Csf2-deficient mice have normal numbers of lymphoid tissue-resident DCs, they display significantly reduced numbers of steady-state nonlymphoid tissue-resident DCs in the small intestine, including the lamina propria CD103+CD11b+ DC subset implicated in the induction of lamina propria Tregs. These results prompted us to further explore the contribution of Csf2 to intestinal immune homeostasis in vivo. We used detailed profiling studies and functional immune assays of the MNP and lymphocyte compartment in the gut, as well as genetically engineered mice that lack Csf2 or the transducer Myd88 specifically in MNPs or lymphocytes, to explore the role of MNPs in the maintenance of immune homeostasis in the gut. Results Our results revealed a crosstalk between IL-1β–secreting MPs and Csf2-producing RORγt+ type 3 innate lymphoid cells (ILC3) in the intestinal mucosa. Microbiota-driven IL-1β production by MPs promoted the release of Csf2 by ILC3, which in turn controlled DCs and MPs to maintain colonic Treg homeostasis. Ablation of Csf2 reduced DC and MP numbers and impaired their ability to produce regulatory factors such as retinoic acid (RA) and IL-10, leading to disrupted Treg homeostasis in the large intestine. Conversely, administration of Csf2 cytokine increased Treg frequency in the gut. Most notably, cell type–specific ablation of IL-1 receptor (IL-1R)–dependent signaling in RORγt+ ILC3 abrogated oral tolerance to dietary antigens and compromised intestinal immune homeostasis in vivo. Although the reduction in Treg numbers was mostly observed in the large intestine, adoptive transfer studies in Csf2–/– mice revealed impaired Treg differentiation both in the small and large intestine, suggesting that Csf2-dependent MNP immunoregulatory functions control Treg induction in both tissues. Conclusion This study established the commensal-driven MNP-ILC-Csf2 axis as a key regulator of intestinal T cell homeostasis in the mouse intestine. Disturbance of this axis radically altered MNP effector function, resulting in impaired oral tolerance to dietary antigens. These results represent an important advance in our understanding of how commensal microbes can regulate host intestinal immunity and may inform the design of novel immunotherapies for patients with inflammatory intestinal diseases with impaired GM-CSF function. Gut Immune Tolerance With the constant assault of food antigens and its billions of resident microbes, the gut is an important site of immune tolerance. By studying specific intestinal immune cell populations in genetically modified mice, Mortha et al. (10.1126/science.1249288, published online 13 March; see the Perspective by Aychek and Jung) found that gut macrophages produce the cytokine interleukin-1 (IL-1) in response to signals derived from the microbiota. IL-1 acts on type 3 innate lymphoid cells in the intestine, which then produce the cytokine, colony-stimulating factor 2 (Csf2). Csf-2, in turn, induces myeloid cells (including dendritic cells and macrophages) to produce regulatory factors like retinoic acid and interleukin-10, which support the conversion and expansion of regulatory T cells, a population of cells known to be critical for maintaining immune tolerance in the gut. Myeloid cells, innate lymphoid cells, and the cytokines they secrete cooperate to maintain immune tolerance in the gut. [Also see Perspective by Aychek and Jung] The intestinal microbiota and tissue-resident myeloid cells promote immune responses that maintain intestinal homeostasis in the host. However, the cellular cues that translate microbial signals into intestinal homeostasis remain unclear. Here, we show that deficient granulocyte-macrophage colony-stimulating factor (GM-CSF) production altered mononuclear phagocyte effector functions and led to reduced regulatory T cell (Treg) numbers and impaired oral tolerance. We observed that RORγt+ innate lymphoid cells (ILCs) are the primary source of GM-CSF in the gut and that ILC-driven GM-CSF production was dependent on the ability of macrophages to sense microbial signals and produce interleukin-1β. Our findings reveal that commensal microbes promote a crosstalk between innate myeloid and lymphoid cells that leads to immune homeostasis in the intestine.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/3e5174f36c1270d402addcbaab3feacc45cab6c2

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In Immunology

1. K. Honda
2. Y. Belkaid
3. A. Mildner
4. Steffen Jung
5. O. Harrison
6. Eric G. Pamer
7. C. Varol
8. Miriam Merad

Citations in the corpus

• Homeostatic immunity and the microbiota (2017, positive): “ILC3 have also been proposed to regulate immune reactivity to the microbiota as MHC-II expressing ILC3 can interact with and delete CD4+ T cells specific for commensal antigens (Hepworth et al., 2015; Hepworth et al., 2013).”
• Cytokine Networks in the Pathophysiology of Inflammatory Bowel Disease. (2019, background): “However, there are opposing effects of GM-CSF in the intestine, including DCmediated stimulation of Foxp3 Treg cell responses (Mortha et al., 2014), suggesting context dependent functions.”
• Innate Lymphoid Cells: a new paradigm in immunology (2015, background): “ILC3s produce lymphotoxins, GM-CSF (granulocyte-macrophage colony-stimulating factor), and IL-22, as well as IL-17 in the fetus, early after birth and during inflammation (57, 58).”
• Innate Lymphoid Cells: 10 Years On. (2018, neutral): “Thus, tissue-resident ILC3s actively regulate macrophage and granulocyte responses to infection through the release of cytokines, such as GM-CSF (Mortha et al., 2014), and by the production of proresolving mediators under vagal system control.”
• Tissue-Resident Macrophage Enhancer Landscapes Are Shaped by the Local Microenvironment (2014, background): “They actively maintain steady state by secreting and responding to cytokines and chemokines (Mortha et al., 2014; Zigmond et al., 2014).”
• Single-Cell Analysis of Crohn’s Disease Lesions Identifies a Pathogenic Cellular Module Associated with Resistance to Anti-TNF Therapy (2019, background): “, 2017), including KIT (CD117), IL23R, IL1R1, the TFs ID2, RORC (RORγt), RORA (RORα) and the cytokines IL22 and CSF2 (GM-CSF) (Figure 2F) (Björklund et al., 2016; Mortha et al., 2014).”
• The Influence of Probiotics on the Firmicutes/Bacteroidetes Ratio in the Treatment of Obesity and Inflammatory Bowel disease (2020, background): “For example, macrophages in the gut sense microbial signals that trigger them to produce interleukin (IL)-1β [65].”
• Macrophages: development and tissue specialization. (2015, background): “More recently, IL-1β produced by intestinal CX3CR1+ macrophages was shown to trigger innate lymphoid cells to secrete CSF-2 and thereby prime and condition the intestinal DC compartment for its interaction with T cells (102).”
• Th17 Cell Induction by Adhesion of Microbes to Intestinal Epithelial Cells (2015, positive): “Among Th17-conducting cytokines, microbiota-induced constitutive and high-level expression of IL-1b was observed in SI LP CD11c+ cells of B6 mice (Figure 4D), which is in line with previous reports (Mortha et al., 2014; Shaw et al., 2012).”
• Antibiotic-Induced Changes in the Intestinal Microbiota and Disease. (2016, background): “Commensal sensing by LPresident phagocytes promotes release of retinoic acid (RA) and IL-10 in mice, leading to the generation and expansion of Tregs, a mechanism that is important in establishing tolerance to food antigens [35].”
• Interleukin-22: immunobiology and pathology (2015, background): “However, this is not true in all models, and IL-22 can induce expression of pro-inflammatory molecules, including IL-1, IL-6, IL-8, IL-11, GCSF, GMCSF, and LPS binding protein (25, 232, 241).”