Research Article

Microbiota-Dependent Crosstalk Between Macrophages and ILC3 Promotes Intestinal Homeostasis

Science  28 Mar 2014:
Vol. 343, Issue 6178,
DOI: 10.1126/science.1249288

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Structured Abstract

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.

Embedded Image

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.

Abstract

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.

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