Reciprocal interactions of the intestinal microbiota and immune system

Abstract

The emergence of the adaptive immune system in vertebrates set the stage for evolution of an advanced symbiotic relationship with the intestinal microbiota. The defining features of specificity and memory that characterize adaptive immunity have afforded vertebrates the mechanisms for efficiently tailoring immune responses to diverse types of microbes, whether to promote mutualism or host defence. These same attributes can put the host at risk of immune-mediated diseases that are increasingly linked to the intestinal microbiota. Understanding how the adaptive immune system copes with the remarkable number and diversity of microbes that colonize the digestive tract, and how the system integrates with more primitive innate immune mechanisms to maintain immune homeostasis, holds considerable promise for new approaches to modulate immune networks to treat and prevent disease.

Figure 1. The gut-associated lymphoid tissues (GALT); establishing perinatal host-microbiota mutualism in the intestine

In utero (prenatal; upper panel), secondary lymphoid tissues [Peyer’s patches (PP) and mesenteric lymph nodes (MLN)], as well as cryptopatches (CP), develop through spatiotemporal recruitment of lymphoid tissue inducer (LTi) cells to sites in the developing intestine and supporting neurovascular structures. The intestinal epithelium is populated by intra-epithelial lymphocytes (IELs) before birth. Bacteria that colonize the neonatal intestine immediately following birth initiate mutiple events that impact development or functional maturation of the mucosa and GALT. Microbe-assoaciated molecular patterns (MAMPs) sensed by patter recognition receptors (PRRs) on intestinal epithelial cells (IECs) and dendritic cells (DCs) adjacent to to cryptopatched (CP) stimultate recruitment of B cells and subsequent maturation of isolated lymphoid follicles (ILFs) (1), which can produce IgA plasma cells via T-dependent and –independent interactions. Increased transport of microbes and their products across the epithelium enter the PP (and ILFs) via M cells (2) before being endocytosed by dendritic cells (DCs) in the subepithelial dome. Antigen-loaded DCs in the PP interact with local lymphocyte subsets to induce T cell differentiation and T-dependent B cell maturation to induce development of IgA-producing plasma cells that home to the lamina propria where they release dimeric IgA for transport into the intestinal lumen. DC-mediated luminal sampling (3) or transcytosis of bacteria across the epithelium (4) results in antigen loading of lamina propria DCs, which migrate via the afferent lymphatics to a draining MLN where they induce differentiation of effector T cells that traffic to the lamina propria. Finally, sensing of MAMPs stimulates the proliferation of IECs in crypts, resulting in their increased depth and, in the small intestine, increased density of Paneth cells and their arming for release of AMPs.

Figure 1. The gut-associated lymphoid tissues (GALT); establishing perinatal host-microbiota mutualism in the intestine

In utero (prenatal; upper panel), secondary lymphoid tissues [Peyer’s patches (PP) and mesenteric lymph nodes (MLN)], as well as cryptopatches (CP), develop through spatiotemporal recruitment of lymphoid tissue inducer (LTi) cells to sites in the developing intestine and supporting neurovascular structures. The intestinal epithelium is populated by intra-epithelial lymphocytes (IELs) before birth. Bacteria that colonize the neonatal intestine immediately following birth initiate mutiple events that impact development or functional maturation of the mucosa and GALT. Microbe-assoaciated molecular patterns (MAMPs) sensed by patter recognition receptors (PRRs) on intestinal epithelial cells (IECs) and dendritic cells (DCs) adjacent to to cryptopatched (CP) stimultate recruitment of B cells and subsequent maturation of isolated lymphoid follicles (ILFs) (1), which can produce IgA plasma cells via T-dependent and –independent interactions. Increased transport of microbes and their products across the epithelium enter the PP (and ILFs) via M cells (2) before being endocytosed by dendritic cells (DCs) in the subepithelial dome. Antigen-loaded DCs in the PP interact with local lymphocyte subsets to induce T cell differentiation and T-dependent B cell maturation to induce development of IgA-producing plasma cells that home to the lamina propria where they release dimeric IgA for transport into the intestinal lumen. DC-mediated luminal sampling (3) or transcytosis of bacteria across the epithelium (4) results in antigen loading of lamina propria DCs, which migrate via the afferent lymphatics to a draining MLN where they induce differentiation of effector T cells that traffic to the lamina propria. Finally, sensing of MAMPs stimulates the proliferation of IECs in crypts, resulting in their increased depth and, in the small intestine, increased density of Paneth cells and their arming for release of AMPs.

Figure 2. The barrier function of the intestinal epithelium

Distinct subpopulations of intestinal epithelial cells (IECs) are integreated into a continuous, single cell layer that is divided into apical and basolateral regions by tight juctions. Although apically expressed toll-like receptors (TLRs) are adapted to limit pro-inflammatory responses at homeostasis, there is on-going sensing of the microbiota to induce the production of anti-microbial peptides (AMPs), both by enterocytes and colonocytes of the the small and large intestine, and specialized Paneth cells in the bases of small intestinal crypts. Goblet cells produce mucin, that is organized into a dense, more highly cross-linked inner proteoglycan gel that forms an IEC-adherent inner mucous layer, and a less densely cross-linked outer mucous layer that is the result of proteolytic cleavage of the predominant intestinal mucin, MUC2. The outer layer is highly colonized by constitutents of the microbiota that attach to and degrade the complex O-linked glycans, providing short-chain fatty acids that are: toxic to potential pathogens; used by IECs as an energy source; and suppress epithelium-induced inflammation. The inner mucous layer is largely impervious to bacterial colonization or penetration, due to its high concentration of bactericidal AMPs, as well as commensal-specific secretory IgA (sIgA), which is ferried across IECs from their basolatral surface, where it is bound by the polymeric immunoglobulin receptor (pIgR), to the inner mucous layer where it is released by proteolytic cleavage of pIgR, apportion of which remins bound to sIgA. Innate lymphoid cells (ILCs), including RORγt- and AhR-expressing LTis and NK-22 cells, respond to microbiota to produce IL-22, an important stimulator of IEC AMP production and epithelial barrier integrity.

Figure 3. The epithelial-innate-adaptive continuum in the immune response to microbial antigens

In response to the microbiota, IECs secrete mucins and AMPs that limit microbial interaction with epithelial cells. Also, under homeostatic, eubiotic conditions, epithelial stimulation by microbiota-derived antigens results in secretion of several cytokines (including TSLP, IL-33, IL-25, and TGFβ) that promote development of tolerogenic macrophages (MΦ) and DCs, which induce development of Treg cells via a TGFβ- and RA-dependent process. Intestinal Treg cells, through multiple mechanisms including secretion of TGFβ and IL-10, the latter of which is also produced by a subset of lamina propria macrophages, maintain an anti-inflammatory tone in the intestines by inhibiting or dampening potential effector responses. In addition, Treg cell-derived TGFβ promotes B cell antibody class-switching to IgA, which, coupled with the T-independent induction of IgA in isolated lymphoid follicles via epithelial-derived BAFF and APRIL, ensures an abundant supply of sIgA in the lumen, further limiting microbial interaction with the epithelium. Conversely, in the face of pathogen invasion or dysbiosis, intestinal DCs and macrophages are the targets of multiple IEC-derived pro-inflammatory cytokines and direct interactions with bacteria and/or their MAMPs that induce the development of effector CD4⁺ T cells, predominantly Th1 and Th17 cells, the latter of which can transition to the former. ILCs in the intestines, including NK-like cells and LTi cells, as well as γδ IELs, respond to cytokine signal derived from IECs and/or myeloid cells (DCs and macrophages) to upregulate cytokines similar to those of effector T cells: IFNγ, IL-17A, and IL-17F, as well as the epithelial barrier protectant, IL-22. Thus, innate cells of the intestinal immune system mediate the equilibrium between anti-inflammatory and pro-inflammatory signals induced by the microbiota under conditions of eubiosis versus dysbiosis, respectively.