Polysaccharide-experienced effector T cells induce IL-10 in FoxP3+ regulatory T cells to prevent pulmonary inflammation

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

doi:10.1093/glycob/cwx093

Cited by 45 publications

(58 citation statements)

References 22 publications

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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%

“…It is therefore interesting to note that the use of both IL-2 and IL-4 appears to be a characteristic of some beneficial microbiota antigen responses. 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%

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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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Section: Resultsmentioning

confidence: 99%

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

Self Cite

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“…Bacteroides fragilis is a gram negative and naturally occurring member of the normal human microbiota and has been robustly demonstrated to have both pro- (10) and anti-inflammatory (7,11,12) effects in rodents. This activity is mediated primarily by its capsular carbohydrate polysaccharide A (PSA) through its ability to elicit a strong T cell response (13) following processing via TLR2-stimulated nitric oxide production (14) and subsequent presentation by canonical class II MHC (MHCII) in a glycosylation-dependent fashion (15,16).…”

Section: Introductionmentioning

confidence: 99%

“…Research focused upon the PSA-responsive T cell population has established that PSA exposure leads to the clonal expansion (21) of a subset of CD4 + CD45Rb low CD62L − CD44 + FoxP3 − T effector/memory (Rb Lo Tem) cells (12,22). These cells suppress asthmatic inflammation in an IL-10-dependent fashion in cooperation with tissue-resident regulatory T cells (Tregs), whereby Tregs are selectively induced to release IL-10 when Rb Lo Tem cells are present (12,22); however, the PSA-stimulated Rb Lo Tem cells are also strong producers of IFNg, the canonical pro-inflammatory cytokine of T helper type 1 cells (Th1) (23).…”

Section: Introductionmentioning

confidence: 99%

Characterization of Polysaccharide A Response Reveals Interferon Responsive Gene Signature and Immunomodulatory Marker Expression

et al. 2020

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Polysaccharide A (PSA), a capsular carbohydrate from the commensal gut bacteria Bacteroides fragilis, has been shown to possess both potent T cell-dependent proand anti-inflammatory properties. PSA is able to induce abscess and adhesion formation in sepsis models, but can also inhibit asthma, inflammatory bowel disease (IBD) and experimental autoimmune encephalomyelitis (EAE) through MHCII-dependent activation of CD4 + T cells. Yet, despite decades of study, the ability of PSA to balance both these pro-and anti-inflammatory responses remains poorly understood. Here, we utilized an unbiased systems immunology approach consisting of RNAseq transcriptomics, highthroughput flow cytometry, and Luminex analysis to characterize the full impact of PSAmediated stimulation of CD4 + T cells. We found that exposure to PSA resulted in the upregulation and secretion of IFNg, TNFa, IL-6, and CXCL10, consistent with an interferon responsive gene (IRG) signature. Importantly, PSA stimulation also led to expression of immune checkpoint markers Lag3, Tim3, and, especially, PD1, which were also enriched and sustained in the gut associated lymphoid tissue of PSA-exposed mice. Taken together, PSA responding cells display an unusual mixture of pro-inflammatory cytokines and anti-inflammatory surface receptors, consistent with the ability to both cause and inhibit inflammatory disease.

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“…However, the animal experiments related to the in‐vivo immunomodulatory effect for LMP were rarely reported. It was accepted that the cell experiments were controllable and less influenced by the environments (Johnson, Jones, & Cobb, ). By contrast, the in‐vivo evaluations are rather complicated.…”

Section: Introductionmentioning

confidence: 99%

Optimization of Maca polysaccharide extraction process and its chemo‐protective effects on cyclophosphamide‐induced mice

Wang

Huang

et al. 2018

J Food Process Engineering

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In this study, the extraction process of Maca polysaccharide (LMP) was deeply studied and its chemo‐protective effects on Cyclophosphamide (Cy)‐induced mice were evaluated. By single factor investigation and response surface methodology optimization, it was found that the liquid‐to‐solid ratio, extraction time, and extraction temperature were the main factors which affected the extraction yield of LMP. The optimum extraction process was obtained by Box–Behnken design combined with response surface methodology. It was found that, at the condition of liquid‐to‐solid ratio of 30:1; extraction time of 2.3 hr; and extraction temperature of 90°C, the yield of the LMP could reach 46.56%. Furthermore, by oral administration of LMP, the cyclophosphamide‐induced mice showed the proliferation of lymphocyte and the phagocytic capacity of macrophages’ enhancements. The number of white blood cell, red blood cell, and platelets in the peripheral blood were up‐regulated; the spleen total superoxide dismutase, Catalase, and Glutathione‐peroxidase activities were enhanced, while the Serum malondialdehyde and Triacylglycerols content was reduced. Therefore, our work provided an effective way for extraction of LMP and demonstrated the chemo‐protective effects of LMP on the animal level. Practical application Natural polysaccharides from functional food sources are widely accepted for their bioactive activities. As extraction conditions significantly affected the quality and yield of polysaccharides, the effective extraction process for polysaccharides should be systematically investigated. In the current work, the optimum conditions for polysaccharides extraction from Maca (Lepidium meyenii Walp.) (LMP) were obtained using liquid‐to‐solid ratio of 30:1 for 2.3 hr at 90°C. The Mass characterization and Monosaccharide Composition of LMP were also determined. Furthermore, the extracted LMP exhibited well Chemo‐protective activities on Cyclophosphamide‐induced mice. Therefore, our work showed the potential applications of Maca polysaccharides as the easily accessible source of natural immunopotentiating agents in function food and pharmaceutical industry.

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Polysaccharide-experienced effector T cells induce IL-10 in FoxP3+ regulatory T cells to prevent pulmonary inflammation

Cited by 45 publications

References 22 publications

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

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

Characterization of Polysaccharide A Response Reveals Interferon Responsive Gene Signature and Immunomodulatory Marker Expression

Optimization of Maca polysaccharide extraction process and its chemo‐protective effects on cyclophosphamide‐induced mice

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