The Multifaceted Influence of the Mucosal Microflora on Mucosal Dendritic Cell Responses

Strober, Warren

doi:10.1016/j.immuni.2009.09.001

Cited by 79 publications

(58 citation statements)

References 87 publications

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“…Multiple studies have implicated TLR signaling by innate immune cells during inflammatory disease (27). Furthermore, TLR2 signaling has been shown to have significant effects on Treg expansion and function (24,25).…”

Section: B F R a G Il Is B F R A G Il Ismentioning

confidence: 99%

Inducible Foxp3 ⁺ regulatory T-cell development by a commensal bacterium of the intestinal microbiota

Round

Mazmanian

2010

Proc. Natl. Acad. Sci. U.S.A.

1,919

1,523

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To maintain intestinal health, the immune system must faithfully respond to antigens from pathogenic microbes while limiting reactions to self-molecules. The gastrointestinal tract represents a unique challenge to the immune system, as it is permanently colonized by a diverse amalgam of bacterial phylotypes producing multitudes of foreign microbial products. Evidence from human and animal studies indicates that inflammatory bowel disease results from uncontrolled inflammation to the intestinal microbiota. However, molecular mechanisms that actively promote mucosal tolerance to the microbiota remain unknown. We report herein that a prominent human commensal, Bacteroides fragilis, directs the development of Foxp3 + regulatory T cells (Tregs) with a unique "inducible" genetic signature. Monocolonization of germ-free animals with B. fragilis increases the suppressive capacity of Tregs and induces anti-inflammatory cytokine production exclusively from Foxp3 + T cells in the gut. We show that the immunomodulatory molecule, polysaccharide A (PSA), of B. fragilis mediates the conversion of CD4 + T cells into Foxp3 + Treg cells that produce IL-10 during commensal colonization. Functional Foxp3 + Treg cells are also produced by PSA during intestinal inflammation, and Toll-like receptor 2 signaling is required for both Treg induction and IL-10 expression. Most significantly, we show that PSA is not only able to prevent, but also cure experimental colitis in animals. Our results therefore demonstrate that B. fragilis co-opts the Treg lineage differentiation pathway in the gut to actively induce mucosal tolerance.Bacteroides fragilis | inflammatory bowel disease | Toll-like receptor | polysaccharide A | interleukin 10

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Section: B F R a G Il Is B F R A G Il Ismentioning

confidence: 99%

Inducible Foxp3 ⁺ regulatory T-cell development by a commensal bacterium of the intestinal microbiota

Round

Mazmanian

2010

Proc. Natl. Acad. Sci. U.S.A.

1,919

1,523

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“…Several subsets of intestinal innate phagocytic cells have recently been identified that modulate intestinal homeostasis (10)(11)(12). In particular, CD103 + CX 3 CR1 − CD11b − dendritic cells (DCs) and CX 3 CR1 + CD11b + DCs have been well characterized (13)(14)(15).…”

mentioning

confidence: 99%

Intestinal CX ₃ C chemokine receptor 1 ^high (CX ₃ CR1 ^high ) myeloid cells prevent T-cell-dependent colitis

Kayama

Ueda

Sawa

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Adequate activation of CD4 + T lymphocytes is essential for host defense against invading pathogens; however, exaggerated activity of effector CD4 + T cells induces tissue damage, leading to inflammatory disorders such as inflammatory bowel diseases. Several unique subsets of intestinal innate immune cells have been identified. However, the direct involvement of innate immune cell subsets in the suppression of T-cell-dependent intestinal inflammation is poorly understood. Here, we report that intestinal CX 3 C chemokine receptor 1 high (CX 3 CR1 high ) CD11b + CD11c + cells are responsible for prevention of intestinal inflammation through inhibition of T-cell responses. These cells inhibit CD4 + T-cell proliferation in a cell contact-dependent manner and prevent T-cell-dependent colitis. The suppressive activity is abrogated in the absence of the IL-10/Stat3 pathway. These cells inhibit T-cell proliferation by two steps. Initially, CX 3 CR1 high CD11b + CD11c + cells preferentially interact with T cells through highly expressed intercellular adhesion molecule-1/vascular cell adhesion molecule-1; then, they fail to activate T cells because of defective expression of CD80/CD86. The IL-10/Stat3 pathway mediates the reduction of CD80/CD86 expression. Transfer of wild-type CX 3 CR1 high CD11b + CD11c + cells prevents development of colitis in myeloid-specific Stat3-deficient mice. Thus, these cells are regulatory myeloid cells that are responsible for maintaining intestinal homeostasis. mucosal immunology | innate immunity

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“…Significantly, the chronic models used to make this conclusion are perhaps more similar to human diseases such as Crohn's disease than the acute models induced by epithelial damage in which pathogenic or protective roles of TLR2 have been identified. Thus modulation of TLR2 function may not be a useful strategy in this condition; however, this does not exclude the possibility that other TLR may play more important roles, as is suggested by the clear need for MyD88 signalling in a variety of colitis models [4] and by the mounting evidence that different TLR can drive very distinct types of response in the intestine and elsewhere [20]. Indeed, even TLR2 can have different functions depending on whether it dimerises with TLR1 or TLR6, with TLR2-TLR1 being proinflammatory and TLR2-TLR6 thought to be anti-inflammatory [21].…”

Section: Discussionmentioning

confidence: 99%

Does TLR2 regulate intestinal inflammation?

Mowat

2010

Eur J Immunol

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There is almost no aspect of the immune response that is not regulated by TLR. Initially described as drivers of the innate immune response to pathogens, it is now clear that the TLR family can also influence most aspects of adaptive immunity, as well as determine how tissue cells interact with microbes in their environment. In particular, the intestine and its immune system must co-exist with an enormous community of commensal bacteria and are also on constant alert against invading pathogens. Unsurprisingly, there is therefore great interest in how TLR might regulate physiological and pathological reactions in the gut. An article in this issue of the European Journal of Immunology addresses this question with some elegant experiments that indicate that TLR2 is not essential for the pathogenesis or T-cell-mediated regulation of different models of inflammatory bowel disease in mice.

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The Multifaceted Influence of the Mucosal Microflora on Mucosal Dendritic Cell Responses

Cited by 79 publications

References 87 publications

Inducible Foxp3 ⁺ regulatory T-cell development by a commensal bacterium of the intestinal microbiota

Inducible Foxp3 ⁺ regulatory T-cell development by a commensal bacterium of the intestinal microbiota

Intestinal CX ₃ C chemokine receptor 1 ^high (CX ₃ CR1 ^high ) myeloid cells prevent T-cell-dependent colitis

Does TLR2 regulate intestinal inflammation?

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The Multifaceted Influence of the Mucosal Microflora on Mucosal Dendritic Cell Responses

Cited by 79 publications

References 87 publications

Inducible Foxp3 + regulatory T-cell development by a commensal bacterium of the intestinal microbiota

Inducible Foxp3 + regulatory T-cell development by a commensal bacterium of the intestinal microbiota

Intestinal CX 3 C chemokine receptor 1 high (CX 3 CR1 high ) myeloid cells prevent T-cell-dependent colitis

Does TLR2 regulate intestinal inflammation?

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Inducible Foxp3 ⁺ regulatory T-cell development by a commensal bacterium of the intestinal microbiota

Inducible Foxp3 ⁺ regulatory T-cell development by a commensal bacterium of the intestinal microbiota

Intestinal CX ₃ C chemokine receptor 1 ^high (CX ₃ CR1 ^high ) myeloid cells prevent T-cell-dependent colitis