Bacterial capsular polysaccharide prevents the onset of asthma through T-cell activation

Abstract

Over the last four decades, increases in the incidence of immune-mediated diseases in the Western world have been linked to changes in microbial exposure. It is becoming increasingly clear that the normal microbiota in the gut can profoundly alter susceptibility to a wide range of diseases, such as asthma, in which immune homeostasis is disrupted, yet the mechanisms governing this microbial influence remains poorly defined. In this study, we show that gastrointestinal exposure to PSA, a capsular polysaccharide derived from the commensal bacterium Bacteroides fragilis, significantly limits susceptibility to the induction of experimental asthma. We report that direct treatment of mice with PSA generates protection from asthma, and this effect can be given to a naïve recipient by adoptive transfer of CD4(+) T cells from PSA-exposed mice. Remarkably, we found that these PSA-induced T cells are not canonical FoxP3(+) regulatory T cells, but that they potently inhibit both Th1 and Th2 models of asthma in an IL-10-dependent fashion. These findings reveal that bacterial polysaccharides link the microbiota with the peripheral immune system by activating CD4(+)Foxp3(-) T cells upon exposure in the gut, and they facilitate resistance to unnecessary inflammatory responses via the production of IL-10.

The influence of gut-derived CD39 regulatory T cells in CNS demyelinating disease

“…34,51,63,64 PSA produced by B. fragilis is protective in models of experimental colitis 65,66 and asthma. 67 The induced IL-10 production that PSA stimulates in T cells is a common feature in the protective mechanism of action, although the phenotype the CD4 + T cell population producing it might actually be disease-specific. 67 Although there are many aspects of the mechanism by which PSA promotes immunomodulation, the polysaccharide is recognized by APCs of the gut in a TLR2 dependent mechanism.…”

“…67 The induced IL-10 production that PSA stimulates in T cells is a common feature in the protective mechanism of action, although the phenotype the CD4 + T cell population producing it might actually be disease-specific. 67 Although there are many aspects of the mechanism by which PSA promotes immunomodulation, the polysaccharide is recognized by APCs of the gut in a TLR2 dependent mechanism. Early studies by Kasper’s laboratory showed that PSA is internalized by dendritic cells that are found next in the mesenteric lymph nodes.…”

The Second Brain: Is the Gut Microbiota a Link Between Obesity and Central Nervous System Disorders?

“…PSA is a capsular polysaccharide that induce regulatory T cells (Tregs) that are immunosuppressive by the production of anti-inflammatory IL-10 [60,61]. PSA also promotes the induction of a subclass of regulatory T cells that express an ectoenzyme, the ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1), also known as CD39, responsible for the catabolism of ATP into AMP (CD39 + Tregs) [62], and also IL-10 producing T cells defined as Tr-1, that are immunosuppressive but do not express the transcription factor foxhead box P3 (FoxP3) that defines Tregs [63-65]. PSA is protective against experimental CNS inflammatory demyelination [60,62,66]: The induction of regulatory T cells by PSA is dependent on the recognition of the polysaccharide by dendritic cells, both conventional [62,63] and plasmacytoid dendritic cells, in a TLR2 dependent mechanims [67].…”

Influence and effect of the human microbiome in allergy and asthma

“…Protected animals possessed a significantly restructured gut microbiome composition and reduced numbers of activated dendritic cells in their mesenteric lymph nodes, suggesting that microbial-mediated alterations to the antigen-presenting cell population represents at least one mechanism of protection against both viral and allergen challenge. Independently, a recent study [30] ] recently demonstrated that mice fed a high-fiber diet exhibited significantly decreased airway allergic response, characterized by reduced interleukin-4, interleukin-5, interleukin-13, and interleukin-17A expression in lung tissue, following intranasal sensitization with HDM (compared with isogenic animals fed a low-fiber diet). Indeed, in mice consuming a high-fiber diet enriched for members of the Bacteroidaceae and Bifidobacteriaceaea in the gut microbiome, including members capable of fermenting fiber to anti-inflammatory SCFAs, an increase in production and circulation of SCFA was observed.…”