Inmune

nature publishing group

REVIEW

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Regulatory mechanisms of immune responses to intestinal bacteria
K Honda1,2,3 and K Takeda1,2
The intestinal mucosa allows the residence of trillions of bacteria with which it interacts dynamically. To establish and maintain a mutually beneficial relationship, the mucosal immune system must enforce tolerance towardthe vast nonpathogenic microbiota while simultaneously remaining reactive to potentially pathogenic microbes; the disruption of this delicate balance results in inflammatory bowel diseases. In this review, we describe advances in our understanding of regulatory mechanisms of the innate immune system and how these shape adaptive immune systems during steadystate and inflammatory processes in theintestinal mucosa.

INTRODUCTION

The gastrointestinal tract is composed of very unique tissue with the presence of commensal bacteria.1 Commensal bacteria colonize the intestinal lumen shortly after birth and comprise approximately 1,000 species with a density of 1012 organisms per milliliter of luminal contents in the large intestine.2–4 The host intestine provides bacteria with amicroenvironment rich in nutrients derived from ingested food. Commensal bacteria, in turn, contribute to the digestion of food, provision of essential nutrients, and prevention of propagation of pathogenic microorganisms.5,6 To maintain these beneficial relationship, the host immune system should remain hypo-responsive to commensal bacteria. However, at the same time, the intestinal immune system has tocombat invasive pathogenic bacteria. Thus, the immune system in the intestinal mucosa has very complicated features that are distinct from that in other tissues. The intestinal immune system mounts a strong inflammation against invasive pathogenic bacteria while providing many layers of inhibitory mechanisms not to mount excessive immune response against commensal bacteria. The breakdown of such adelicate balance of the intestinal immune system causes the development of inflammatory bowel diseases (IBDs).7,8 Accordingly, the regulatory mechanisms of immune responses to intestinal bacteria have recently been a subject of intensive research.
REGULATION OF TLR SIGNALING IN THE INTESTINE

Among some of the most impressive progress in the field of immunology in the last decade has been theelucidation of the

mechanisms for innate immune recognition of microorganisms.9 Innate immunity specifically recognizes molecular patterns of microorganisms through Toll-like receptors (TLRs) and other pattern-recognition receptors, and use of pattern-recognition receptors helps regulate the development of antigen-specific adaptive immune responses.10–12 Functional characterization of TLRs hasmade us aware that TLR-dependent responses at the intestinal mucosa should be finely regulated. Macrophages isolated from the intestinal lamina propria of healthy humans and mice have been shown to be hypo-responsive to TLR stimulation.13–16 In contrast, substantial amounts of TLR-dependent cytokine production can be observed in intestinal lamina propria macrophages from hosts with intestinalinflammation.13,14 For example, macrophages from interleukin (IL)-10-deficient mice and myeloid cell-specific Stat3-deficient mice, both of which spontaneously develop intestinal inflammation, are in a state of constitutive and aberrant activation.17 In these mutant mice, blockade of the TLR signaling by the introduction of deficiency in TLR4 or MyD88 abrogates the development of intestinalinflammation,18,19 indicating that TLR-dependent excessive inflammatory responses at the intestinal mucosa causes development of colitis. In addition, as with the murine model of intestinal inflammation, a unique subset of macrophages with excess TLR-dependent inflammatory responses were observed in the lamina propria of IBD patients.20–22 Thus, negative regulation of TLR-dependent responses in intestinal...