Polysaccharide A from the Capsule of Bacteroides fragilis Induces Clonal CD4+ T Cell Expansion

Johnson, Jenny L.; Jones, Mark B.; Cobb, Brian A.

doi:10.1074/jbc.m114.621771

Cited by 63 publications

(35 citation statements)

References 27 publications

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“…The production of IL-10 is primarily mediated by DCs , which internalize PSA and present fragments to CD4 + T cells in conjunction with the major histocompatibility complex class II (MHC-II), thus stimulating activation and clonal expansion of T cells. Importantly, PSA also activates toll-like receptor (TLR) 2 expressed on the surface of DCs, which triggers the release of cytokines that promote IL-10 production by T cells (Cobb et al, 2004; Dasgupta et al, 2014; Johnson et al, 2015; Mazmanian et al, 2005; 2008; Telesford et al, 2015; Q. Wang et al, 2006).…”

Section: Microbiome-associated Metabolites That Shape the Immune Systemmentioning

confidence: 99%

Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System

2017

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SUMMARY The human gastrointestinal tract is populated by a diverse, highly mutualistic microbial flora, which is known as the microbiome. Disruptions to the microbiome have been shown to be associated with severe pathologies of the host including metabolic disease, cancer and inflammatory bowel disease. Mood and behavior are also susceptible to alterations in the gut microbiota. A particularly striking example of the symbiotic effects of the microbiome is the immune system, whose cells depend critically on a diverse array of microbial metabolites for normal development and behavior. This includes metabolites that are produced by bacteria from dietary components; metabolites that are produced by the host and biochemically modified by gut bacteria; and metabolites that are synthesized de novo by gut microbes. In this review, we highlight the role of the intestinal microbiome in human metabolic and inflammatory diseases and focus in particular on the molecular mechanisms that govern the gut-immune axis.

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Section: Microbiome-associated Metabolites That Shape the Immune Systemmentioning

confidence: 99%

Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System

2017

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“…PSA–TLR2 activation of pDCs and Treg cell induction can also mediate protection in extra‐intestinal inflammatory diseases such as experimental autoimmune encephalomyelitis, a multiple sclerosis animal model . Additional work characterizing PSA‐induced Treg cell activation via MHCII‐mediated antigen presentation suggests that the interaction depends on the zwitterionic (carries positive and negative charges) properties of PSA and induces a specific clonal expansion of Treg cells . Lactobacillus plantarum teichoic acid d ‐alanylation (component of Gram‐positive bacterial envelope) also signals through TLR2 and promotes a pro‐inflammatory cytokine response in DCs, which modulates effector and regulatory T‐cell populations (Fig.…”

Section: Bacterial Components That Effect Innate and Adaptive Immunitymentioning

confidence: 99%

Microbiota and host immune responses: a love–hate relationship

2015

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SummaryA complex relationship between the microbiota and the host emerges early at birth and continues throughout life. The microbiota includes the prokaryotes, viruses and eukaryotes living among us, all of which interact to different extents with various organs and tissues in the body, including the immune system. Although the microbiota is most dense in the lower intestine, its influence on host immunity extends beyond the gastrointestinal tract. These interactions with the immune system operate through the actions of various microbial structures and metabolites, with outcomes ranging from beneficial to deleterious for the host. These differential outcomes are dictated by host factors, environment, and the type of microbes or products present in a specific ecosystem. It is also becoming clear that the microbes are in turn affected and respond to the host immune system. Disruption of this complex dialogue between host and microbiota can lead to immune pathologies such as inflammatory bowel diseases, diabetes and obesity. This review will discuss recent advances regarding the ways in which the host immune system and microbiota interact and communicate with one another.

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“…Given the potent in vitro Treg response to the combination of IL-2 and IL-4 and the resulting integration of their signaling pathways, we next sought to determine the in vivo response within the context of inflammatory disease. Since this pathway was implicated using murine asthma ( 29, 37–39 ), we first challenged mice with house dust mite (HDM) over the course of 2 weeks to induce pulmonary inflammation as described previously ( 29 ). The combinatorial cytokines were administered i.n.…”

Section: Resultsmentioning

confidence: 99%

“…For example, Bacteroides fragilis, which is native to a healthy human gut ( 48, 49 ), is known to regulate the peripheral immune system ( 37, 38, 50, 51 ) and even benefit the gut-brain axis ( 52, 53 ) through T cell recognition of its capsular polysaccharide PSA ( 54 ). It is now clear that PSA-specific effector T cells require communication with Tregs, and that immune suppression and inflammatory disease reversal depends upon both IL-4 ( 29, 39 ) and IL-2 ( 55 ), thereby providing a biological context in which the use of cytokines in combination has evolved to direct a healthy immune tone.…”

Section: Discussionmentioning

confidence: 99%

Integration of IL-2 and IL-4 Signals Coordinates Divergent Regulatory T cell Responses and Drives Therapeutic Efficacy

Zhou

Álvarez

Cobb

2020

Preprint

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19Cells exist within complex milieus of communicating factors, such as cytokines, that combine to 20 generate context-specific responses, yet nearly all knowledge about the function of each cytokine and 21 the signaling propagated downstream of their recognition is based upon the response to individual 22cytokines. Here, we found that regulatory T cells (Tregs) integrate concurrent signaling initiated by IL-2 23and IL-4 to generate a response divergent from the sum of the two pathways in isolation. IL-4 24 stimulation of STAT6 phosphorylation was blocked by IL-2, while IL-2 and IL-4 synergized to enhance 25 STAT5 phosphorylation, IL-10 production, and the selective proliferation of IL-10-producing Tregs, 26leading to increased inhibition of conventional T cell activation and the reversal of asthma and multiple 27 sclerosis in mice. These data define a mechanism of combinatorial cytokine signaling and lay the 28 foundation upon which to better understand the origins of cytokine pleiotropy while informing 29improved the clinical use of cytokines. 30 picture of cytokine pleiotropy and potentially leading to enhancements to the use of cytokines in the 77 clinical setting. 78 79 Results 80 IL-2 and IL-4 synergistically promote IL-10 production by Tregs 81Our previous findings demonstrated that IL-4 impacts IL-10 production in FoxP3 + Tregs (29), but the 82 nature of the functional interaction between IL-4 and IL-2, a key survival factor for Tregs in vitro and in 83 vivo, remained obscure. Thus, we created a novel dual reporter mouse by crossing FoxP3 RFP (30) and IL-84 10 GFP (31) mice, thereby enabling live sorting of FoxP3 + cells and analysis of IL-10 production on a per-cell 85 basis. CD4 + FoxP3 + Tregs isolated from the spleens of naïve dual reporter mice (Figure 1 -figure 86 supplement 1A-B) by magnetic bead and sterile fluorescence-activated cell sorting (FACS) were cultured 87 with T cell receptor (TCR) activation using αCD3ε antibody and all combinations of IL-2 and IL-4 for 3 88 days. We found that Tregs cultured with combinatorial cytokine stimulation resulted in synergistically 89higher numbers of IL-10 expressing cells (Figures 1A-1C) and IL-10 secretion ( Figure 1D) compared to 90 single cytokine stimulation. However, analysis of IL-10 + cells revealed that IL-10 expression was no 91 different than IL-2-stimulation in isolation ( Figure 1E), suggesting that the cytokines in combination do 92 not elicit a synergistic increase in IL-10 production on a per-cell basis. The sex-independent ( Figure 1F) 93and TCR-stimulation dependent synergy ( Figures 1A-1D) was present in FoxP3 + Tregs but not FoxP3 -94Tconv ( Figure 1A), and no loss of FoxP3 expression was observed ( Figure 1G), suggesting that the 95 machinery required for this effect was unique to FoxP3 + Tregs. 96In order to determine whether the cytokines must be present at the same time, we isolated Tregs 97 and stimulated them with cytokines in series over a 3-day culture and compared the response to 98 simultaneous stimulation. We discovered that b...

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Polysaccharide A from the Capsule of Bacteroides fragilis Induces Clonal CD4+ T Cell Expansion

Abstract: Background: Zwitterionic polysaccharides activate CD4ϩ T cells via MHCII presentation.

Cited by 63 publications

References 27 publications

Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System

Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System

Microbiota and host immune responses: a love–hate relationship

Integration of IL-2 and IL-4 Signals Coordinates Divergent Regulatory T cell Responses and Drives Therapeutic Efficacy

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