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1.
Int Immunol ; 30(4): 155-169, 2018 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-29420746

RESUMO

The incidence of allergic diseases, which increased to epidemic proportions in developed countries over the last few decades, has been correlated with altered gut microbiota colonization. Although probiotics may play a critical role in the restoration of gut homeostasis, their efficiency in the control of allergy is controversial. Here, we aimed to investigate the effects of probiotic treatment initiated at neonatal or adult ages on the suppression of experimental ovalbumin (OVA)-induced asthma. Neonatal or adult mice were orally treated with probiotic bacteria and subjected to OVA-induced allergy. Asthma-like symptoms, microbiota composition and frequencies of the total CD4+ T lymphocytes and CD4+Foxp3+ regulatory T (Treg) cells were evaluated in both groups. Probiotic administration to neonates, but not to adults, was necessary and sufficient for the absolute prevention of experimental allergen-induced sensitization. The neonatally acquired tolerance, transferrable to probiotic-untreated adult recipients by splenic cells from tolerant donors, was associated with modulation of gut bacterial composition, augmented levels of cecum butyrate and selective accumulation of Treg cells in the airways. Our findings reveal that a cross-talk between a healthy microbiota and qualitative features inherent to neonatal T cells, especially in the Treg cell subset, might support the beneficial effect of perinatal exposure to probiotic bacteria on the development of long-term tolerance to allergens.


Assuntos
Asma/etiologia , Asma/prevenção & controle , Imunomodulação , Microbiota , Probióticos/administração & dosagem , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Adulto , Alérgenos/imunologia , Animais , Antígenos/imunologia , Asma/diagnóstico , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Recém-Nascido , Camundongos , Gravidez
2.
Immun Inflamm Dis ; 4(4): 474-486, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27980781

RESUMO

INTRODUCTION: A tight balance between regulatory CD4+Foxp3+ (Treg) and conventional CD4+Foxp3- (Tconv) T cell subsets in the peripheral compartment, maintained stable throughout most of lifetime, is essential for preserving self-tolerance along with efficient immune responses. An excess of Treg cells, described for aged individuals, may critically contribute to their reported immunodeficiency. In this work, we investigated if quantitative changes in thymus emigration may alter the Treg/Tconv homeostasis regardless of the aging status of the peripheral compartment. METHODS: We used two different protocols to modify the rate of thymus emigration: thymectomy of adult young (4-6 weeks old) mice and grafting of young thymus onto aged (18 months old) hosts. Additionally, lymphoid cells from young and aged B6 mice were intravenously transferred to B6.RAG2-/- mice. Alterations in Treg and Tconv peripheral frequencies following these protocols were investigated after 30 days by flow cytometry. RESULTS: Thymectomized young mice presented a progressive increase in the Treg cell frequency, while the grafting of a functional thymus in aged mice restored the young-like physiological Treg/Tconv proportion. Strikingly, T cells derived from young or aged splenocytes colonized the lymphopenic periphery of RAG-/- hosts to the same extent, giving rise to similarly elevated Treg cell levels irrespective of the age of the donor population. In the absence of thymus output, the Treg subset seems to survive longer, as confirmed by their lower proportion of Annexin-V+ cells. CONCLUSIONS: Our data suggest that the thymus-emigrating population, harboring an adequate proportion of Treg/Tconv lymphocytes, may be essential to keep the Treg cell balance, independently of age-related shifts intrinsic to the peripheral environment or to the T cell biology.


Assuntos
Homeostase , Subpopulações de Linfócitos T , Linfócitos T Reguladores/fisiologia , Timo/fisiologia , Animais , Tolerância Imunológica , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Tolerância a Antígenos Próprios
3.
Immunology ; 147(2): 221-39, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26572097

RESUMO

CD4(+) Foxp3(+) regulatory T (Treg) cells are necessary for the maintenance of self-tolerance and T-cell homeostasis. This population is kept at stable frequencies in secondary lymphoid organs for the majority of the lifetime, despite permanent thymic emigration or in the face of thymic involution. Continuous competition is expected to occur between recently thymus-emigrated and resident Treg cells (either natural or post-thymically induced). In the present work, we analysed the renewal dynamics of Treg cells compared with CD4(+) Foxp3- conventional T cells (Tconv), using protocols of single or successive T-cell transfers into syngeneic euthymic or lymphopenic (nu/nu or RAG2(-/-)) mice, respectively. Our results show a higher turnover for Treg cells in the peripheral compartment, compared with Tconv cells, when B cell-sufficient euthymic or nude hosts are studied. This increased renewal within the Treg pool, shown by the greater replacement of resident Treg cells by donor counterparts, correlates with augmented rates of proliferation and is not modified following temporary environmental perturbations induced by inflammatory state or microbiota alterations. Notably, the preferential substitution of Treg lymphocytes was not observed in RAG2(-/-) hosts. We showed that limited B-cell replenishment in the RAG2(-/-) hosts decisively contributed to the altered peripheral T-cell homeostasis. Accordingly, weekly transfers of B cells to RAG2(-/-) hosts rescued the preferential substitution of Treg lymphocytes. Our study discloses a new aspect of T-cell homeostasis that depends on the presence of B lymphocytes to regulate the relative incorporation of recently arrived Treg and Tconv cells in the peripheral compartment.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Proliferação de Células , Linfócitos T Reguladores/imunologia , Transferência Adotiva , Animais , Antibacterianos/farmacologia , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/microbiologia , Linfócitos T CD4-Positivos/transplante , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Genótipo , Homeostase , Interações Hospedeiro-Patógeno , Inflamação/imunologia , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Nus , Microbiota/imunologia , Fenótipo , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/microbiologia , Linfócitos T Reguladores/transplante , Fatores de Tempo
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