Immune adaptations that maintain homeostasis with the intestinal microbiota

KEY POINTS * The human intestine contains ∼100 trillion bacteria that make essential contributions to human metabolism and establish symbiotic relationships with their hosts. However, these

organisms pose an ongoing threat of invasion owing to their enormous numbers. * The intestinal immune system has evolved unique immune adaptations that allow it to manage its high bacterial

load. These immune mechanisms work together to ensure that commensal bacteria rarely breach the intestinal barrier and that any that do invade are killed rapidly and do not penetrate to

systemic sites. * A key element of the mammalian intestinal strategy for maintaining homeostasis with the microbiota is to minimize contact between luminal microorganisms and the intestinal

epithelial cell surface. This is accomplished by enhancing the physical barrier through the production of mucus, antimicrobial proteins and IgA. * A second layer of intestinal immune

protection relies on the rapid detection and killing of bacteria that penetrate the epithelial cell surface. This occurs by several immune mechanisms, including bacterial uptake and

phagocytosis by innate immune cells and a complex set of T cell-mediated responses. * A third immune barrier is presented by the mesenteric lymph nodes, which constitute an immune

'firewall' limiting penetration by commensal microorganisms to the systemic immune system. This allows induction of adaptive immune responses to resident bacteria to be confined to

the mucosal immune compartment. * An increasing amount of evidence suggests that inflammatory bowel disease (IBD) arises from dysregulated control of host–microorganism interactions. In

support of this hypothesis, several IBD risk alleles compromise intestinal immune mechanisms that maintain homeostasis with the microbiota. ABSTRACT Humans harbour nearly 100 trillion

intestinal bacteria that are essential for health. Millions of years of co-evolution have moulded this human–microorganism interaction into a symbiotic relationship in which gut bacteria

make essential contributions to human nutrient metabolism and in return occupy a nutrient-rich environment. Although intestinal microorganisms carry out essential functions for their hosts,

they pose a constant threat of invasion owing to their sheer numbers and the large intestinal surface area. In this Review, we discuss the unique adaptations of the intestinal immune system

that maintain homeostatic interactions with a diverse resident microbiota. Access through your institution Buy or subscribe This is a preview of subscription content, access via your

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* Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS DIVERSITY AND DYNAMISM OF IGA−MICROBIOTA INTERACTIONS Article 10

February 2021 LONG-DISTANCE RELATIONSHIPS - REGULATION OF SYSTEMIC HOST DEFENSE AGAINST INFECTIONS BY THE GUT MICROBIOTA Article 22 June 2022 UNCONVENTIONAL IMMUNE CELLS IN THE GUT MUCOSAL

BARRIER: REGULATION BY SYMBIOTIC MICROBIOTA Article Open access 11 September 2023 CHANGE HISTORY * _ 07 APRIL 2015 In figure 4 of the original article, the cytokines that promote the

differentiation of T helper 2 (TH2) cells and TH17 cells were included in the wrong order. This has now been corrected in the online HTML and PDF versions of the article. Nature Reviews

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laboratory for the many discussions that contributed to the ideas in this manuscript. Work in L.V.H.'s laboratory is supported by the Howard Hughes Medical Institute, the US National

Institutes of Health (DK070855), the Burroughs Wellcome Foundation and the Crohn's and Colitis Foundation. A.M. acknowledges K. McCoy, E. Slack, S. Hapfelmeier, M. Stoehl and M.

Geuking. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * The Howard Hughes Medical Institute and The Department of Immunology, The University of Texas Southwestern Medical Center, Dallas,

75390, Texas, USA Lora V. Hooper * The Department of Clinical Research (DFK), Maurice Müller Laboratories, Universitätsklinik für Viszerale Chirurgie und Medizin (UVCM), University of Bern,

3008, Bern, Switzerland Andrew J. Macpherson * Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, L8S 4L8, Ontario, Canada Andrew J. Macpherson Authors *

Lora V. Hooper View author publications You can also search for this author inPubMed Google Scholar * Andrew J. Macpherson View author publications You can also search for this author

inPubMed Google Scholar ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. RELATED LINKS RELATED LINKS FURTHER INFORMATION Lora V. Hooper's

homepage Andrew J. Macpherson's homepage GLOSSARY * Microbiota The microorganisms that are harboured by normal, healthy individuals. These microorganisms live in the digestive tract and

at other body sites. * Sepsis A systemic response to severe infection or tissue damage, leading to a hyperactive and unbalanced network of pro-inflammatory mediators. Vascular permeability,

cardiac function and metabolic balance are affected, resulting in tissue necrosis, multi-organ failure and death. * Metagenome All the genetic material present in a population of

microorganisms, consisting of the genomes of many individual organisms. * Goblet cell A mucus-producing cell found in the epithelial cell lining of the intestine and lungs. * Defensin A

class of antimicrobial peptide that has activity against Gram-positive and Gram-negative bacteria, fungi and viruses. α-defensins are produced by intestinal Paneth cells and neutrophils, and

β-defensins are expressed by most epithelial cells. * C-type lectin An animal receptor protein that binds to carbohydrates, frequently in a Ca2+-dependent manner. The binding activity of

C-type lectins is based on the structure of the carbohydrate-recognition domain, which is highly conserved among members of this family. * Paneth cells A specialized epithelial cell lineage

that produces most of the antimicrobial proteins in the small intestine. * Peyer's patches Groups of lymphoid nodules present in the small intestine (usually the ileum). They occur

massed together on the intestinal wall, opposite the line of attachment of the mesentery. Peyer's patches consist of a dome area, B cell follicles and interfollicular T cell areas. High

endothelial venules are present mainly in the interfollicular areas. * Lamina propria Connective tissue that underlies the epithelium of the mucosa and contains various myeloid and lymphoid

cells, including macrophages, dendritic cells, T cells and B cells. * Plasma cell A non-dividing, terminally differentiated, immobile antibody-secreting cell of the B cell lineage. *

Transcytosis Process of transport of material across a cell monolayer by uptake on one side of the cell into a coated vesicle, which might then be sorted through the _trans_-Golgi network

and transported to the opposite side of the cell. * Germ-free mouse A mouse that is born and raised in isolators, without exposure to microorganisms. * Germinal centre Located in peripheral

lymphoid tissues (for example, the spleen), these structures are sites of B cell proliferation and selection for clones that produce antigen-specific antibodies of higher affinity. *

Recombination-activating gene (_Rag_). A gene expressed by developing lymphocytes. Mice that are deficient for either _Rag1_ or _Rag2_ fail to produce B or T cells owing to a developmental

block in the gene rearrangement that is necessary for antigen receptor expression. * Severe combined immunodeficiency (SCID). A phenotype of mice with a defect in DNA recombination. SCID

mice lack B and T cells and do not reject tissue grafts from allogeneic and xenogeneic sources. * Intraepithelial CD8αα+ T cell A type of T cell that is found in the intestinal epithelium.

The CD8 molecule that they express is a homodimer of CD8α, rather than the CD8αβ heterodimer that is expressed by conventional CD8+ T cells in the lymph nodes. It has been proposed that

these cells are self-reactive T cells that have regulatory properties. * Lymphoid-tissue inducer cell (LTi cell). A cell that is present in developing lymph nodes, Peyer's patches and

nasopharynx-associated lymphoid tissue. LTi cells are required for the development of these lymphoid organs and are characterized by expression of the transcription factor retinoic acid

receptor-related orphan receptor-γt (RORγt), interleukin-7 receptor-α and lymphotoxin-α1β;2. * Specific pathogen-free (SPF) mice Mice kept in specific vivarium conditions whereby a number of

pathogens are excluded or eradicated from the colony. These animals are maintained in the absence of most of the known chronic and latent persistent pathogens. Although this enables better

control of experimental conditions related to immunity and infection, it also sets apart such animal models from pathogen-exposed humans or non-human primates, whose immune systems are in

constant contact with potential pathogens. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Hooper, L., Macpherson, A. Immune adaptations that maintain

homeostasis with the intestinal microbiota. _Nat Rev Immunol_ 10, 159–169 (2010). https://doi.org/10.1038/nri2710 Download citation * Issue Date: March 2010 * DOI:

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