Intestinal Antigen-Presenting Cells: Key Regulators of Immune Homeostasis and Inflammation

Abstract

The microbiota that populate the mammalian intestine are critical for proper host physiology, yet simultaneously pose a potential danger. Intestinal antigen-presenting cells, namely macrophages and dendritic cells (DCs), are integral components of the mucosal innate immune system that maintain co-existence with the microbiota in face of this constant threat. Intestinal macrophages and DCs integrate signals from the microenvironment to orchestrate innate and adaptive immune responses that ultimately lead to durable tolerance of the microbiota. Tolerance is not a default response, however, because macrophages and DCs remain poised to vigorously respond to pathogens that breach the epithelial barrier. In this review, we summarize the salient features of macrophages and DCs in the healthy and inflamed intestine and discuss how signals from the microbiota can influence their function.

Figure 1

Distinguishing characteristics of mouse intestinal macrophages (MΦ) and dendritic cells (DCs). Colony-stimulating factor 1 (Csf1) favors the differentiation of intestinal macrophages from macrophages and DC progenitors (MDPs), whereas FMS-like tyrosine kinase 3 ligand (Flt3L) and colony-stimulating factor 2 (Csf2) enhance the differentiation of MDPs into the DC lineage. After populating the intestine, macrophages and DCs can be identified by various cell surface markers. Antigens expressed predominantly by intestinal macrophages include F4/80, CX3CR1, CD14, and CD64, whereas intestinal DCs express CD103, CD272, CD26, and CCR7. Additional markers, including CD45, major histocompatibility complex (MHC) II, CD11b, and CD11c, overlap across both cell types. Macrophages and DCs in the intestine also exhibit a functional dichotomy. Intestinal macrophages are avidly phagocytic and constitutively produce IL-10, in contrast to intestinal DCs, which efficiently migrate to mesenteric lymph nodes (mLNs) and produce lower levels of IL-10.

Figure 2

The function of intestinal macrophages (MΦ) and dendritic cells (DCs) in the steady state and during inflammation/injury. In the steady state, resident CX3CR1⁺ macrophages and CD103⁺ DCs maintain tolerance toward the intestinal microbiota via the production of retinoic acid and IL-10, which, in combination with transforming growth factor (TGF)-β, induce regulatory T cells (Treg) cells. On encountering certain bacteria, CD103⁺ DCs can also produce IL-6 and IL-23, which drive type 17 helper T-cell (Th17) differentiation in a TGF-β–dependent manner. During inflammation/injury, Ly6C⁺CCR2⁺ monocytes are recruited into the intestine, where they, along with resident DCs, react to translocating bacteria through innate signaling pathways [eg, Toll-like receptor (TLR)]. These signals drive proinflammatory cytokine production, including IL-1β, tumor necrosis factor (TNF), IL-12, and IL-23, which can promote pathogenic Th1 and Th17 responses.

Figure 3

Microbial factors condition intestinal macrophages (MΦ) and dendritic cells (DCs) to promote unique T-cell responses. Different members of the microbiota and their components can stimulate intestinal macrophages and/or DCs to induce regulatory T cells (Tregs) or type 17 helper T cells (Th17). Macrophages secrete IL-1β in response to commensal bacteria, prompting the production of colony-stimulating factor 2 (Csf2) from type 3 innate lymphoid cells (ILC3s). Csf2 can then engage macrophages and DCs to produce regulatory molecules (eg, retinoic acid and IL-10) involved in the induction of Treg cells. Polysaccharide A (PSA), expressed by Bacteroides fragilis and commensal-derived short-chain fatty acids (SCFAs), can also act on intestinal macrophages and DCs to stimulate retinoic acid and IL-10 production, and induce Treg cell differentiation. Segmented filamentous bacteria (SFB) can gain close contact with the intestinal epithelium, initiating signaling programs that drive the secretion of IL-6 and IL-23 from macrophages and DCs, leading to Th17 differentiation. ATP derived from commensal bacteria can bind receptors on intestinal macrophages and/or DCs, leading to enhanced IL-6 and IL-23 expression and the induction of Th17 cells. Both Treg and Th17 differentiation also require transforming growth factor (TGF)-β, which is constitutively expressed in the intestine. mLN, mesenteric lymph node; pDC, plasmacytoid dendritic cell.