Epigenetic regulation in murine offspring as a novel mechanism for transmaternal asthma protection induced by microbes

Brand, Stéphanie; Teich, René; Dicke, Tanja; Harb, Hani; Yildirim, Ali Önder; Tost, Jörg; Schneider‐Stock, Regine; Waterland, Robert A.; Bauer, Uta‐Maria; Mutius, Erika von; Garn, Holger; Pfefferle, Petra Ina; Renz, Harald

doi:10.1016/j.jaci.2011.04.035

Cited by 164 publications

(128 citation statements)

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“…For ChIP experiments, CD8 + T cells enriched by negative MACS selection were preactivated with plate-bound anti-CD3 mAb (2 μg/mL) and soluble anti-CD28 mAb (1 μg/mL) in the presence of rhIL-2 (50 units/mL) for 3 d, rested overnight, and stimulated with IL-21 (100 ng/mL) for 1 h. A total of 2 × 10 6 cells were fixed with 1% formaldehyde for 10 min at room temperature to preserve the protein-DNA interactions. Subsequently, ChIP was performed as described previously (38) with antibodies against IRF4 (M-17; Santa Cruz). Quantitative RT-PCR with the precipitated chromatin was performed to calculate the percentage of input.…”

Section: Discussionmentioning

confidence: 99%

“…On day 5 p.i., WT or Irf4 −/− OT-I CD8 + T cells were recovered from spleens of recipient mice by MACS purification and equalized numbers of cells (1 × 10 6 ) were transferred into naive mice. One day later, target and control cells were prepared by loading of spleen cells with 10 −6 M of the peptides OVA 257-264 (target cells) or LCMV gp [33][34][35][36][37][38][39][40][41] (control cells), which were then stained with 2 μM or 0.2 μM CFSE, respectively. Target and control cells were then mixed in a 1:1 ratio and a total of 6 × 10 6 cells were injected into the recipients of activated OT-I cells.…”

Section: Discussionmentioning

confidence: 99%

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The transcription factor Interferon Regulatory Factor 4 is required for the generation of protective effector CD8 ⁺ T cells

Raczkowski

Ritter

Heesch

et al. 2013

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

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Robust cytotoxic CD8 + T-cell response is important for immunity to intracellular pathogens. Here, we show that the transcription factor IFN Regulatory Factor 4 (IRF4) is crucial for the protective CD8 + T-cell response to the intracellular bacterium Listeria monocytogenes. IRF4-deficient (Irf4 −/− ) mice could not clear L. monocytogenes infection and generated decreased numbers of L. monocytogenesspecific CD8 + T cells with impaired effector phenotype and function. Transfer of wild-type CD8 + T cells into Irf4 −/− mice improved bacterial clearance, suggesting an intrinsic defect of CD8 + T cells in Irf4 −/− mice. Following transfer into wild-type recipients, Irf4 −/− CD8 + T cells became activated and showed initial proliferation upon L. monocytogenes infection. However, these cells could not sustain proliferation, produced reduced amounts of IFN-γ and TNF-α, and failed to acquire cytotoxic function. Forced IRF4 expression in Irf4 −/− CD8 + T cells rescued the defect. During acute infection, Irf4 −/− CD8 + T cells demonstrated diminished expression of B lymphocyte-induced maturation protein-1 (Blimp-1), inhibitor of DNA binding (Id)2, and T-box expressed in T cells (T-bet), transcription factors programming effector-cell generation. IRF4 was essential for expression of Blimp-1, suggesting that altered regulation of Blimp-1 contributes to the defects of Irf4 −/− CD8 + T cells. Despite increased levels of B-cell lymphoma 6 (BCL-6), Eomesodermin, and Id3, Irf4 −/− CD8 + T cells showed impaired memory-cell formation, indicating additional functions for IRF4 in this process. As IRF4 governs B-cell and CD4 + T-cell differentiation, the identification of its decisive role in peripheral CD8 + T-cell differentiation, suggests a common regulatory function for IRF4 in adaptive lymphocytes fate decision.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The transcription factor Interferon Regulatory Factor 4 is required for the generation of protective effector CD8 ⁺ T cells

Raczkowski

Ritter

Heesch

et al. 2013

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

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“…Furthermore, both transmaternal allergoprotection and prevention of airway allergic inflammation have been recently demonstrated as depending on the epigenetic control of the IFNG promoter but not on modifications of IL-10 levels. 35,36 Several undesirable effects have been related to the triggering of TLRs. Innate receptor signaling has been associated with lung inflammation and T H 17 response related to disease severity in asthmatic patients.…”

Section: Discussionmentioning

confidence: 99%

A novel allergen-adjuvant conjugate suitable for specific immunotherapy of respiratory allergy

Filì¹,

Vultaggio²,

Cardilicchia³

et al. 2013

Journal of Allergy and Clinical Immunology

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Background: Several approaches to find a better adjuvant, focus immunomodulation, and reduce allergenicity are under investigation to improve the efficacy and safety of specific immunotherapy. Objective: We performed an investigation of the in vitro and in vivo effects of a purified allergen chemically conjugated to a novel 8-OH modified adenine as an adjuvant. Methods: Purified group 2 major allergen from house dust mite chemically conjugated to 4-(6-amino-9-benzyl-8-hydroxy-9H-purin-2-ylsulfanyl)-butyric acid succinimidyl ester was analyzed by using mass spectrometry. The adduct (nDer p 2-Conj) was assayed for Toll-like receptor activation on transfected HEK293 cells, stimulation of innate cells, and effects on the functional phenotype of specific T-cell lines and clones by means of flow cytometry, real-time PCR, and expression of T H -related transcription factors. Lung cells and sera of nDer p 2-Conjsensitized C57Bl/6 mice were studied by means of cytology, histology, real-time PCR, and ELISA. Results: nDer p 2-Conj stimulated IL-12 and IFN-a production from monocytes and plasmacytoid dendritic cells, respectively, retaining the ability to trigger Toll-like receptor 7 exclusively, and expanded human allergen-specific lymphocytes with reduced ability to produce T H 2-related cytokines and increased IFN-g levels, as based on GATA-3/T-bet expression. In vivo adduct-sensitized mice exhibited reduced eosinophil infiltration and IL-13 expression in the airways, IFN-g upregulation together with IgE downregulation, and an increase in allergenspecific IgG 2a levels in sera. The conjugate exhibited reduced ability to activate human FcεRI 1 cells without inducing T H 17 cells or autoantibodies.

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“…Thus, epigenetic regulation has been suggested as one of the underlying effector mechanisms for the allergy preventive effect of microbial exposure during pregnancy [91].…”

Section: Lactobacillus Reuteri and Toll-like Receptorsmentioning

confidence: 99%

Lactobacillus reuteri, Infant Allergy Prevention and Childhood Immune Maturation

Forsberg¹

2016

Probiotics and Prebiotics in Human Nutrition and Health

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The increasing allergy prevalence in affluent countries may be caused by reduced microbial stimulation, resulting in an abnormal postnatal immune maturation. This chapter concerns the theories behind the use of probiotics in randomized prevention trials, and how this supplementation affects the immunity of pregnant women, the immune development in their children, and possibly preventing allergic diseases. Most studies investigating the underlying mechanisms have focused on postnatal microbial exposure. An increasing body of evidence from studies suggests that the maternal microbial environment during pregnancy can program the immune development of the child. In human allergy intervention studies, probiotic supplementation to the mother during pregnancy, as well as to her baby postnatally, may be important for preventive effects. Also, prenatal environmental exposures may alter gene expression via epigenetic mechanisms, aiming to induce physiological adaptations to the anticipated postnatal environment. The maternal microbial environment during pregnancy may program the immune development of the child.

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Epigenetic regulation in murine offspring as a novel mechanism for transmaternal asthma protection induced by microbes

Cited by 164 publications

References 42 publications

The transcription factor Interferon Regulatory Factor 4 is required for the generation of protective effector CD8 ⁺ T cells

The transcription factor Interferon Regulatory Factor 4 is required for the generation of protective effector CD8 ⁺ T cells

A novel allergen-adjuvant conjugate suitable for specific immunotherapy of respiratory allergy

Lactobacillus reuteri, Infant Allergy Prevention and Childhood Immune Maturation

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Epigenetic regulation in murine offspring as a novel mechanism for transmaternal asthma protection induced by microbes

Cited by 164 publications

References 42 publications

The transcription factor Interferon Regulatory Factor 4 is required for the generation of protective effector CD8 + T cells

The transcription factor Interferon Regulatory Factor 4 is required for the generation of protective effector CD8 + T cells

A novel allergen-adjuvant conjugate suitable for specific immunotherapy of respiratory allergy

Lactobacillus reuteri, Infant Allergy Prevention and Childhood Immune Maturation

Contact Info

Product

Resources

About

The transcription factor Interferon Regulatory Factor 4 is required for the generation of protective effector CD8 ⁺ T cells

The transcription factor Interferon Regulatory Factor 4 is required for the generation of protective effector CD8 ⁺ T cells