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The love–hate relationship between bacterial polysaccharides and the host immune system

Key Points

  • For many years, it has been understood that commensal bacteria contribute to the development of the gut-associated lymphoid tissue. Recently, it has been shown that certain systemic immune functions are also impaired in the absence of commensal bacteria.

  • Bacteroides fragilis, a commensal bacterium that is found in all mammals, synthesizes zwitterionic polysaccharides (ZPSs), which are unique in structure and function compared with all other known bacterial polysaccharides. Unlike other polysaccharides, ZPSs activate CD4+ T cells specifically and are therefore T-cell-dependent antigens.

  • ZPSs contain both a positively and a negatively charged motif in each repeating unit. This property is required for the interactions of ZPSs with the immune system.

  • The unique chemical structure of ZPSs mediates their uptake by professional antigen-presenting cells (APCs), directs their processing in the endosomes of APCs and contributes to their presentation to CD4+ T cells by MHC class II molecules. Therefore, ZPSs are non-peptide antigens that bind MHC class II molecules and induce immune responses.

  • ZPSs protect laboratory animals from T-cell-mediated pathologies such as abscess formation and fibrosis, through inducing production of the anti-inflammatory molecule interleukin-10.

  • Colonization of germ-free animals with B. fragilis corrects several immune defects that are found in the absence of bacteria, including a reduction in the proportion of the total splenic lymphocyte population that consists of CD4+ T cells, incomplete development of the spleen and imbalanced production of T helper 1 (TH1) and TH2 cytokines. ZPSs are necessary and sufficient for correcting these defects.

  • The 'hygiene hypothesis' states that recent societal changes have altered our natural exposure to bacteria, with consequent increases in the rates of certain immune and atopic disorders. ZPSs might be the missing link in our understanding of the molecular basis of the increase in incidence of allergic disorders, such as inflammatory bowel disease and asthma.

Abstract

This article explores the fascinating relationship between the mammalian immune system and the bacteria that are present in the mammalian gut. Every human is an ecosystem that hosts 1013–1014 bacteria. We review the evidence that immunomodulatory molecules produced by commensal bacteria in the gut have a beneficial influence on the development of certain immune responses, through eliciting the clonal expansion of CD4+ T-cell populations. This process seems to contribute to the overall health of the host by offering protection against various diseases and might provide supporting evidence at a molecular level for the 'hygiene hypothesis' of allergic immune disorders.

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Figure 1: Immune-cell activation by polysaccharides.
Figure 2: Structure of polysaccharide A of Bacteroides fragilis and proposed interactions of polysaccharide A with MHC class II molecules.
Figure 3: Antigen presentation of polysaccharide A of Bacteroides fragilis.
Figure 4: Impact of polysaccharide A of Bacteroides fragilis on development of a mature mammalian immune system.

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Acknowledgements

We thank J. McCoy for editorial advice. S.K.M. acknowledges fellowships from the Helen Hay Whitney Foundation (USA) and The William Randolph Hearst Foundations (USA). Work in D.L.K.'s laboratory is supported by funding from the National Institutes of Health (USA). Work in S.K.M.'s laboratory is supported by funding from the Crohn's and Colitis Foundation of America. We apologize to the many authors whose work could not be mentioned owing to space constraints.

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Glossary

Immunoglobulin class switching

The somatic-recombination process by which the class of immunoglobulin expressed by naive B cells is switched from IgM to IgG, IgA or IgE on exposure to antigen.

Obligate anaerobe

An anaerobic organism can grow in the absence of oxygen. Obligate anaerobes die when exposed to atmospheric levels of oxygen, unlike facultative anaerobes, which can use oxygen when it is present.

Sterile caecal contents

A preparation of the cell-free material that is present in the caecum of the gastrointestinal tract. The preparation contains all of the soluble materials that are released by commensal bacteria but does not contain viable organisms.

Immunodominance

The result of an antigen(s) within a complex mixture (such as whole virus) or an epitope(s) within a protein being preferentially recognized during an immune response.

HLA-DM

An MHC-class-II-like molecule that facilitates the formation of high-affinity peptide–MHC complexes through the release of MHC-class-II-associated invariant-chain peptide (CLIP) in endosomes. The release of CLIP allows the binding of peptides derived from phagocytosed particles for presentation to CD4+ T cells.

Immunological synapse

A region that can form between two cells of the immune system that are in close contact. This region was named the immunological synapse because of similarities to the synapses that occur in the nervous system; it originally referred only to the interaction between a T cell and an antigen-presenting cell. The immunological synapse involves adhesion molecules, as well as antigen receptors and cytokine receptors.

Gut-associated lymphoid tissue

(GALT). The tissues and cells that constitute the immune system associated with the gastrointestinal tract. This system includes structures such as the Peyer's patches, inducible lymphoid follicles, cryptopatches and the mesenteric lymph nodes, as well as circulating and non-circulating immune cells of the lamina propria, and intra-epithelial lymphocytes.

Germ-free mice

Animals that are born and raised in sterile isolator chambers and are devoid of colonization by any foreign microorganisms, including bacteria, viruses, fungi and protozoa. The experimental colonization of animals with known microorganisms (an approach that is known as gnotobiology) allows the effect of a specific microorganism on the biological functions of an animal to be investigated.

Lymphoid follicles

Anatomical zones in the primary or secondary lymphoid tissues that contain aggregates of lymphocytes, mainly B cells, which are surrounded by T cells. Follicles might also contain structures known as germinal centres, which are areas of proliferating and differentiating B cells.

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Mazmanian, S., Kasper, D. The love–hate relationship between bacterial polysaccharides and the host immune system. Nat Rev Immunol 6, 849–858 (2006). https://doi.org/10.1038/nri1956

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