Regulation of innate and adaptive immunity by the commensal microbiota

Abstract

The microbial communities that inhabit the intestinal tract are essential for mammalian health. Communication between the microbiota and the host establishes and maintains immune homeostasis, enabling protective immune responses against pathogens while preventing adverse inflammatory responses to harmless commensal microbes. Specific bacteria, such as segmented filamentous bacteria, Clostridium species, and Bacteroides fragilis, are key contributors to immune homeostasis in the gut. The cellular and molecular interactions between intestinal microbes and the immune system are rapidly being elucidated. Here, we review advances in our understanding of the microbial populations that shape the mucosal immune system and create a protective defense that prevents infection while tolerating friendly commensals.

Figure 1

Major mechanisms that may contribute to the restoration of colonization resistance. Antibiotic treatment results in depletion of the normal microbiota, rendering the host susceptible to colonization by potentially pathogenic microbes. Recovery of a commensal microbiota by adoptive transfer or cohousing with normal mice restores colonization resistance, leading to clearance of dangerous bacteria such as S. typhimurium and VRE. Two major mechanisms may contribute to pathogen clearance: the direct effect of the commensal flora on the growth of the pathogen (A) and restoration of immune tone induced by stimulation of immune receptors, preventing expansion of the pathogen (B and C). The mechanisms underlying direct pathogen inhibition by the microbiota remain ill-defined, but may include competition for nutritional resources and production of growth inhibitory molecules. As depicted in B, bacterial products stimulate innate immune receptors expressed on epithelial cells to restore immune homeostasis in the intestine. The production of RegIIIγ, an antimicrobicidal lectin that targets Gram-positive bacteria, by intestinal epithelial cells, helps maintain homeostasis of intestinal microbial communities and contributes to clearance of invading species such as VRE. RegIIIγ is elicited by direct sensing of the microbiota by intestinal epithelial cells (B) or, when bacterial products are found systemically, by sensing of bacterial products by cells of hematopoietic origin that express IL-22 (C). Following disruption of the epithelium, bacteria and their products reach the lamina propria and stimulate innate immune receptors, which recruits and activates neutrophils and monocytes, and stimulates IgA responses (C). Immune cells of the lamina propria are activated to generate an antimicrobial program that clears the pathogen and restores health to the epithelial barrier.

Figure 2

The microbiota induces Th17 cell expansion through multiple mechanisms. SFB induces expression of serum amyloid A (SAA) in the small intestine, which leads to DC-mediated Th17 differentiation (A). ATP (adenosine 5′ triphosphate), which can be produced by the microbiota, contributes to Th17 differentiation by activating a subset of DC via a MyD88- and TRIF-independent mechanism (B). Flagellin-mediated stimulation of TLR5 expressed on CD103⁺ lamina propria DC induces IL-6 expression, contributing to the Th17 cell program (C). Phagocytosis of infected apoptotic cells by dendritic cells contributes to the production of Th17-inducing cytokines (D). Several DC subsets are present in the intestinal lamina propria, which may respond distinctly to these signals, contributing to Th17 cell expansion. The frequency of Th17 cells in the intestine is negatively regulated by microbiota-induced production of IL-25 by intestinal epithelial cells, which limits IL-23 production (E).