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1.
Clin Exp Allergy ; 47(10): 1331-1341, 2017 Oct.
Article in English | MEDLINE | ID: mdl-28802077

ABSTRACT

BACKGROUND: Food allergy is an increasingly common health problem in Western populations. Epidemiological studies have suggested both positive and negative associations between food allergy and infection with the gastric bacterium Helicobacter pylori. OBJECTIVE: The objective of this work was to investigate whether experimental infection with H. pylori, or prophylactic treatment with H. pylori-derived immunomodulatory molecules, affects the onset and severity of food allergy, either positively or negatively. METHODS: We infected neonatal C57BL/6 or C3H mice with H. pylori or treated animals with H. pylori components (bacterial lysate or the immunomodulator VacA) and subsequently subjected them to four different protocols for food allergy induction, using either ovalbumin or peanut extract as allergens for sensitization and challenge. Readouts included anaphylaxis scoring, quantification of allergen-specific serum IgE and IgG1 and of the mast cell protease MCPT1, as well as splenic T-helper-2 cell-derived cytokine production. Mesenteric lymph node CD4+ FoxP3+ regulatory T cells were subjected to flow cytometric quantification and sorting followed by qRT-PCR, and to DNA methylation analyses of the Treg-specific demethylated region (TSDR) within the FOXP3 locus. RESULTS: Mice that had been infected with H. pylori or treated with H. pylori-derived immunomodulators showed reduced anaphylaxis upon allergen sensitization and challenge, irrespective of the allergen used. Most of the immunologic assays confirmed a protective effect of H. pylori. CD4+ FoxP3+ T cells were more abundant in protected mice and exhibited a stable Treg phenotype characterized by FOXP3 TSDR demethylation. CONCLUSIONS AND CLINICAL RELEVANCE: Helicobacter pylori confers protection against the anaphylaxis associated with ovalbumin and peanut allergy and affects the epigenome of T cells, thereby promoting stable Treg differentiation and functionality. Prophylactic treatment with H. pylori-derived immunomodulators appears to be a promising strategy for food allergy prevention.


Subject(s)
Anaphylaxis/prevention & control , Bacterial Proteins/immunology , Food Hypersensitivity/prevention & control , Helicobacter pylori/immunology , Immunologic Factors/immunology , Allergens/immunology , Anaphylaxis/genetics , Anaphylaxis/immunology , Anaphylaxis/metabolism , Animals , CpG Islands , Cytokines/blood , Cytokines/metabolism , DNA Methylation , Disease Models, Animal , Food Hypersensitivity/genetics , Food Hypersensitivity/immunology , Food Hypersensitivity/metabolism , Immunoglobulin E/immunology , Male , Mice , Peanut Hypersensitivity/genetics , Peanut Hypersensitivity/immunology , Peanut Hypersensitivity/metabolism , Peanut Hypersensitivity/prevention & control , Spleen/cytology , Spleen/immunology , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism
2.
Mucosal Immunol ; 10(6): 1443-1454, 2017 11.
Article in English | MEDLINE | ID: mdl-28198363

ABSTRACT

The concept of a "topographical memory" in lymphocytes implies a stable expression of homing receptors mediating trafficking of lymphocytes back to the tissue of initial activation. However, a significant plasticity of the gut-homing receptor α4ß7 was found in CD8+ T cells, questioning the concept. We now demonstrate that α4ß7 expression in murine CD4+ memory T cells is, in contrast, imprinted and remains stable in the absence of the inducing factor retinoic acid (RA) or other stimuli from mucosal environments. Repetitive rounds of RA treatment enhanced the stability of de novo induced α4ß7. A novel enhancer element in the murine Itga4 locus was identified that showed, correlating to stability, selective DNA demethylation in mucosa-seeking memory cells and methylation-dependent transcriptional activity in a reporter gene assay. This implies that epigenetic mechanisms contribute to the stabilization of α4ß7 expression. Analogous DNA methylation patterns could be observed in the human ITGA4 locus, suggesting that its epigenetic regulation is conserved between mice and men. These data prove that mucosa-specific homing mediated by α4ß7 is imprinted in CD4+ memory T cells, reinstating the validity of the concept of "topographical memory" for mucosal tissues, and imply a critical role of epigenetic mechanisms.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , Integrin alpha4/metabolism , Intestines/immunology , Receptors, Lymphocyte Homing/metabolism , T-Lymphocyte Subsets/immunology , Animals , Cell Movement , Cells, Cultured , DNA Methylation , Enhancer Elements, Genetic/genetics , Epigenesis, Genetic , Gene Expression Regulation , Immunologic Memory , Integrin alpha4/genetics , Integrin beta Chains/metabolism , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Tretinoin/metabolism
3.
Mucosal Immunol ; 9(2): 444-57, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26307665

ABSTRACT

Foxp3 (forkhead box P3 transcription factor)-expressing regulatory T cells (Tregs) are essential for immunological tolerance, best illustrated by uncontrolled effector T-cell responses and autoimmunity upon loss of Foxp3 expression. Tregs can adopt specific effector phenotypes upon activation, reflecting the diversity of functional demands in the different tissues of the body. Here, we report that Foxp3(+)CD4(+) T cells coexpressing retinoic acid-related orphan receptor-γt (RORγt), the master transcription factor for T helper type 17 (Th17) cells, represent a stable effector Treg lineage. Transcriptomic and epigenetic profiling revealed that Foxp3(+)RORγt(+) T cells display signatures of both Tregs and Th17 cells, although the degree of similarity was higher to Foxp3(+)RORγt(-) Tregs than to Foxp3(-)RORγt(+) T cells. Importantly, Foxp3(+)RORγt(+) T cells were significantly demethylated at Treg-specific epigenetic signature genes such as Foxp3, Ctla-4, Gitr, Eos, and Helios, suggesting that these cells have a stable regulatory rather than inflammatory function. Indeed, adoptive transfer of Foxp3(+)RORγt(+) T cells in the T-cell transfer colitis model confirmed their Treg function and lineage stability in vivo, and revealed an enhanced suppressive capacity as compared with Foxp3(+)RORγt(-) Tregs. Thus, our data suggest that RORγt expression in Tregs contributes to an optimal suppressive capacity during gut-specific immune responses, rendering Foxp3(+)RORγt(+) T cells as an important effector Treg subset in the intestinal system.


Subject(s)
Colitis/immunology , Forkhead Transcription Factors/immunology , Immunity, Mucosal/drug effects , Nuclear Receptor Subfamily 1, Group F, Member 3/immunology , T-Lymphocytes, Regulatory/immunology , Adoptive Transfer , Animals , CTLA-4 Antigen/genetics , CTLA-4 Antigen/immunology , Carrier Proteins/genetics , Carrier Proteins/immunology , Cell Lineage , Colitis/genetics , Colitis/pathology , Colon/immunology , Colon/pathology , DNA-Binding Proteins/genetics , DNA-Binding Proteins/immunology , Epigenesis, Genetic/immunology , Female , Forkhead Transcription Factors/genetics , Glucocorticoid-Induced TNFR-Related Protein/genetics , Glucocorticoid-Induced TNFR-Related Protein/immunology , Inflammation , Lymphocyte Activation , Mice , Mice, Inbred C57BL , Mice, Knockout , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/immunology , Nuclear Receptor Subfamily 1, Group F, Member 3/genetics , Signal Transduction , T-Lymphocytes, Regulatory/pathology , T-Lymphocytes, Regulatory/transplantation , Transcription Factors/genetics , Transcription Factors/immunology
4.
Allergy ; 70(12): 1656-60, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26228301

ABSTRACT

Regulatory T cells (Tregs) are known to play critical roles in homeostasis and immune responses in the skin. Whether Treg frequencies are altered in atopic dermatitis (AD) patients has been addressed by several studies, leading to conflicting results. The detection of Tregs by FOXP3 expression may lead to false-positive results as activated T cells without regulatory function may transiently upregulate this transcription factor. In contrast, measurement of the DNA methylation status of a region within the FOXP3 locus that is selectively demethylated only in bona fide Tregs (Treg-specific demethylated region, TSDR) represents a reliable method to quantify Tregs. Here, we measured circulating Treg frequencies of adult patients and detected a positive correlation with disease severity. Subsequent surface marker analysis revealed higher frequencies of CD45RA(+) CCR7(-) tissue-homing Tregs in the patient group with a tendency of reduced expression of CD39 compared with healthy donors, a marker for the highly suppressive TREM subtype.


Subject(s)
Dermatitis, Atopic/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Regulatory/immunology , Adult , Female , Flow Cytometry , Forkhead Transcription Factors/immunology , Humans , Immunophenotyping , Male
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