Regulatory T Cell Reprogramming toward a Th2-Cell-like Lineage Impairs Oral Tolerance and Promotes Food Allergy

Rivas, Magali Noval; Burton, Oliver T.; Wise, Petra; Charbonnier, Louis-Marie; Georgiev, Peter; Oettgen, Hans C.; Rachid, Rima; Chatila, Talal A.

doi:10.1016/j.immuni.2015.02.004

Cited by 307 publications

(246 citation statements)

References 50 publications

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“…7, 8 Other studies also suggest that Treg cells are involved in controlling the development and resolution of allergic diseases. 9–13 Accordingly, the balance between the activation of Th2-type immunity and the regulatory activity of Treg cells may play a pivotal role in the evolution of allergic airway diseases.…”

Section: Introductionmentioning

confidence: 99%

“…29 More recently, “Th2 cell-like” Treg cells have been identified in the intestine and secondary lymphoid organs in a mouse model of food allergy involving a gain-of-function IL-4Rα chain allele. 9 In humans, Treg cells that express type 2 cytokines, such as IL-4 and IL-13, were detected in the skin of patients with systemic sclerosis. 30 Thus, Treg cells are likely altered when influenced by certain tissue microenvironments.…”

Section: Introductionmentioning

confidence: 99%

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IL-33 dysregulates regulatory T cells and impairs established immunologic tolerance in the lungs

Chen

Kobayashi

Izutsu

et al. 2017

Journal of Allergy and Clinical Immunology

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Background Airway exposure to environmental antigens generally leads to immunological tolerance. A fundamental question remains: why is airway tolerance compromised in patients with allergic airway diseases? Interleukin (IL)-33 promotes innate and adaptive type 2 immunity and may provide the answer to this question. Objective The goal of this study was to investigate the roles IL-33 plays in altering regulatory T (Treg) cells in the lungs and in affecting previously established airway immunological tolerance. Methods We analyzed CD4+ forkhead box p3 (Foxp3)+ Treg cells that were isolated from the lungs of naïve BALB/c mice and those treated with IL-33. Airway tolerance and allergen-induced airway inflammation models in mice were used to investigate how IL-33 affects established immunological tolerance in vivo. Results CD4+Foxp3+ Treg cells in the lungs expressed IL-33 receptor ST2. When exposed to IL-33, Treg cells upregulated their expression of canonical Th2 transcription factor GATA3 as well as ST2, and produced type 2 cytokines. Treg cells lost their ability to suppress effector T cells in the presence of IL-33. Airway administration of IL-33 with an antigen impaired the immunological tolerance in the lungs that had been established by prior exposure to the antigen. Dysregulated Foxp3+ Treg cells with distinct characteristics of Th2 cells increased in the lungs of the mice undergoing IL-33-dependent allergen-driven airway inflammation. Conclusions IL-33 dysregulated lung Treg cells and impaired immunological tolerance to inhaled antigens. Established airway tolerance may not be sustained in the presence of an innate immunological stimulation, such as IL-33.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

IL-33 dysregulates regulatory T cells and impairs established immunologic tolerance in the lungs

Chen

Kobayashi

Izutsu

et al. 2017

Journal of Allergy and Clinical Immunology

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“…Oral anaphylaxis is hard to achieve in most mouse models; therefore different challenge strategies are used, and systemic anaphylaxis is commonly monitored as the readout. In mice, the decrease in core body temperature after systemic, cutaneous, or intragastric allergen challenges is monitored by rectal or subcutaneous probes 35, 36. In addition, allergic diarrhea can be scored by assessing the stool viscosity and stool hemorrhage, and they have been used as another readout for intestinal anaphylactic responses.…”

Section: Pathophysiology Of Human Food Allergy As Reflected In Murinementioning

confidence: 99%

“…It can therefore be concluded that constitutive activation of the IL4Rα can circumvent the tolerance pathways by providing the IL4R signaling achieved in other models with adjuvants such as cholera toxin 57 . Allergic patients fail to develop oral tolerance to their allergen in part because of a defect in the generation of Tregs, which are not only vital to tolerance of the adaptive immune system but have been shown to have a direct effect on mast cells by blocking degranulation 35, 58, 59, 60. The IL4RF709 mice can reproduce this absence to produce allergen-specific Tregs 35 .…”

Section: Adjuvant-free Oral Sensitization or Spontaneous Sensitizatiomentioning

confidence: 99%

Experimental Models for Studying Food Allergy

Kanagaratham

Sallis

Fiebiger

2018

Cellular and Molecular Gastroenterology and Hepatology

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Immunoglobulin E–mediated food allergy is rapidly developing into a global health problem. Publicly available therapeutic intervention strategies are currently restricted to allergen avoidance and emergency treatments. To gain a better understanding of the disease pathophysiology so that new therapies can be developed, major research efforts have been put into studying food allergy in mice. Animal models should reflect the human pathology as closely as possible to allow for a rapid translation of basic science observations to the bedside. In this regard, experimental models of food allergy provide significant challenges for research because of discrepancies between the presentation of disease in humans and mice. The goal of this review is to give a summary of commonly used murine disease models and to discuss how they relate to the human condition. We will focus on epicutaneous sensitization models, on mouse strains that sensitize spontaneously to food as seen in humans, and on models in humanized animals. In summary, expanding the research toolbox of experimental food allergy provides an important step toward closing gaps in our understanding of the derailing immune mechanism that underlies the human disease. The availability of additional experimental models will provide exciting opportunities to discover new intervention points for the treatment of food allergies. (Cell Mol Gastroenterol Hepatol 2018;x:x)

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“…IL-4 receptor signaling has been shown to impair the capacity of Tregs to suppress mast cell activation and expansion, which in turn drives Th2-cell reprogramming of Tregs [39] . Moreover, IL-4 inhibits mouse CD5 + B1 cells from adopting a macrophage-like morphology [38] .…”

Section: Foxp3mentioning

confidence: 99%

Oral tolerance is inducible during active dextran sulfate sodium-induced colitis

Ino

Kohda

Takeshima

et al. 2016

WJGPT

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AIM:To investigate whether oral tolerance is inducible during the active phase of dextran sulfate sodium (DSS)-induced colitis. METHODS:Colitis was induced in 6-to 8-wk-old female BALB/c mice by the administration of 2% DSS. To induce oral tolerance, mice that received water with DSS [DSS (+)] and mice that received autoclaved water [DSS (-) Hiroshi Takahashi, Division of Gastroenterology, Department of Internal Medicine, Showa University, Yokohama 227-8501, JapanAuthor contributions: Ino S, Kohda C and Takeshima K performed the majority of experiments and analyzed the data; Norose T, Yamochi T and Takimoto M contributed pathological analysis; Kohda C, Ishikawa H, Takahashi H and Tanaka K designed and coordinated the research; Ino S and Kohda C wrote the paper.Institutional review board statement: All procedures involving experimental animals were approved by the Institutional Animal Care and Use Committee of Showa University (Permit Number: 04127) and complied with the Guide for the Care and Use of Laboratory Animals (7 th and 8 th edition, ILAR-NRC). In our facility, the Animal Care and Use Committee of Showa University also functions as an Institutional Review Board for animal experiments.Institutional animal care and use committee statement: All procedures involving experimental animals were approved by the Institutional Animal Care and Use Committee of Showa University (Permit Number: 04127) and complied with the Guide for the Care and Use of Laboratory Animals (7 th and 8 th edition, ILAR-NRC). Conflict-of-interest statement:To the best of our knowledge, no conflict of interest exists.Data sharing statement: A technical appendix, statistical code, and dataset are available from the corresponding author at kohda@med.showa-u.ac.jp. All participants provided informed consent for data sharing. ORIGINAL ARTICLE Foxp3+ cell and B10 cell frequencies were evaluated using flow cytometry. Cytokine mRNA expression profiles were evaluated by reverse transcription real-time polymerase chain reaction. RESULTS:Regardless of the presence of DSS colitis, OVA-specific immunoglobulin E concentrations were significantly reduced in mice that were i.g. administered OVA compared to mice that were i.g. administered PBS[DSS (+): 4.4 (4.2-9.5) ng/mL vs 83.9 (66.1-123.2) ng/mL, P < 0.01; DSS (-): 27.7 (0.1-54.5) ng/mL vs 116.5 (80.6-213.6) ng/mL, P < 0.01]. These results demonstrated that oral tolerance was induced in both the presence and absence of colitis. In the spleen and mesenteric lymph nodes (MLN), the frequencies of CD4 + CD25 + Foxp3 + cells and B10 cells, both of which are associated with oral tolerance, did not significantly change. In the spleen, interferon-γ mRNA expression significantly decreased in mice with colitis [DSS (+): 0.42 (0.31-0.53) vs DSS (-): 1.00 (0.84-1.39), P < 0.01]. The expression levels of other cytokines did not significantly change. CONCLUSION:Oral tolerance is inducible during active DSS colitis. The stability of regulatory cell populations in the spleen and MLN in colitis might correla...

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Regulatory T Cell Reprogramming toward a Th2-Cell-like Lineage Impairs Oral Tolerance and Promotes Food Allergy

Cited by 307 publications

References 50 publications

IL-33 dysregulates regulatory T cells and impairs established immunologic tolerance in the lungs

IL-33 dysregulates regulatory T cells and impairs established immunologic tolerance in the lungs

Experimental Models for Studying Food Allergy

Oral tolerance is inducible during active dextran sulfate sodium-induced colitis

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