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Loss- and Gain-of-Function Approaches Indicate a Dual Role Exerted by Regulatory T Cells in Pulmonary Paracoccidioidomycosis

Paracoccidioidomycosis (PCM), is a pulmonary fungal disease whose severity depends on the adequate development of T cell immunity. Although regulatory T (Treg) cells were shown to control immunity against PCM, deleterious or protective effects were described in different experimental settings. To cl...

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Autores principales: Bazan, Silvia B., Costa, Tania A., de Araújo, Eliseu Frank, Feriotti, Claudia, Loures, Flávio V., Pretel, Fernando D., Calich, Vera L. G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4626087/
https://www.ncbi.nlm.nih.gov/pubmed/26512987
http://dx.doi.org/10.1371/journal.pntd.0004189
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author Bazan, Silvia B.
Costa, Tania A.
de Araújo, Eliseu Frank
Feriotti, Claudia
Loures, Flávio V.
Pretel, Fernando D.
Calich, Vera L. G.
author_facet Bazan, Silvia B.
Costa, Tania A.
de Araújo, Eliseu Frank
Feriotti, Claudia
Loures, Flávio V.
Pretel, Fernando D.
Calich, Vera L. G.
author_sort Bazan, Silvia B.
collection PubMed
description Paracoccidioidomycosis (PCM), is a pulmonary fungal disease whose severity depends on the adequate development of T cell immunity. Although regulatory T (Treg) cells were shown to control immunity against PCM, deleterious or protective effects were described in different experimental settings. To clarify the function of Treg cells in pulmonary PCM, loss-and gain-of-function approaches were performed with Foxp3(GFP) knock-in mice and immunodeficient Rag1(-/-) mice, respectively, which were intratracheally infected with 10(6) yeast cells. The activity of Foxp3-expressing Treg cells in pulmonary PCM was determined in Foxp3(GFP) transgenic mice. First, it was verified that natural Treg cells migrate to the lungs of infected mice, where they become activated. Depletion of Treg cells led to reduced fungal load, diminished pathogen dissemination and increased Th1/Th2/Th17 immunity. Further, adoptive transfer of diverse T cell subsets to Rag1(-/-) mice subsequently infected by the pulmonary route demonstrated that isolated CD4(+)Foxp3(+) Treg cells were able to confer some degree of immunoprotection and that CD4(+)Foxp3(-) T cells alone reduced fungal growth and enhanced T cell immunity, but induced vigorous inflammatory reactions in the lungs. Nevertheless, transfer of Treg cells combined with CD4(+)Foxp3(-) T cells generated more efficient and balanced immune Th1/Th2/Th17 responses able to limit pathogen growth and excessive tissue inflammation, leading to regressive disease and increased survival rates. Altogether, these loss- and gain-of-function approaches allow us to clearly demonstrate the dual role of Treg cells in pulmonary PCM, their deleterious effects by impairing T cell immunity and pathogen eradication, and their protective role by suppressing exacerbated tissue inflammation.
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spelling pubmed-46260872015-11-06 Loss- and Gain-of-Function Approaches Indicate a Dual Role Exerted by Regulatory T Cells in Pulmonary Paracoccidioidomycosis Bazan, Silvia B. Costa, Tania A. de Araújo, Eliseu Frank Feriotti, Claudia Loures, Flávio V. Pretel, Fernando D. Calich, Vera L. G. PLoS Negl Trop Dis Research Article Paracoccidioidomycosis (PCM), is a pulmonary fungal disease whose severity depends on the adequate development of T cell immunity. Although regulatory T (Treg) cells were shown to control immunity against PCM, deleterious or protective effects were described in different experimental settings. To clarify the function of Treg cells in pulmonary PCM, loss-and gain-of-function approaches were performed with Foxp3(GFP) knock-in mice and immunodeficient Rag1(-/-) mice, respectively, which were intratracheally infected with 10(6) yeast cells. The activity of Foxp3-expressing Treg cells in pulmonary PCM was determined in Foxp3(GFP) transgenic mice. First, it was verified that natural Treg cells migrate to the lungs of infected mice, where they become activated. Depletion of Treg cells led to reduced fungal load, diminished pathogen dissemination and increased Th1/Th2/Th17 immunity. Further, adoptive transfer of diverse T cell subsets to Rag1(-/-) mice subsequently infected by the pulmonary route demonstrated that isolated CD4(+)Foxp3(+) Treg cells were able to confer some degree of immunoprotection and that CD4(+)Foxp3(-) T cells alone reduced fungal growth and enhanced T cell immunity, but induced vigorous inflammatory reactions in the lungs. Nevertheless, transfer of Treg cells combined with CD4(+)Foxp3(-) T cells generated more efficient and balanced immune Th1/Th2/Th17 responses able to limit pathogen growth and excessive tissue inflammation, leading to regressive disease and increased survival rates. Altogether, these loss- and gain-of-function approaches allow us to clearly demonstrate the dual role of Treg cells in pulmonary PCM, their deleterious effects by impairing T cell immunity and pathogen eradication, and their protective role by suppressing exacerbated tissue inflammation. Public Library of Science 2015-10-29 /pmc/articles/PMC4626087/ /pubmed/26512987 http://dx.doi.org/10.1371/journal.pntd.0004189 Text en © 2015 Bazan et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Bazan, Silvia B.
Costa, Tania A.
de Araújo, Eliseu Frank
Feriotti, Claudia
Loures, Flávio V.
Pretel, Fernando D.
Calich, Vera L. G.
Loss- and Gain-of-Function Approaches Indicate a Dual Role Exerted by Regulatory T Cells in Pulmonary Paracoccidioidomycosis
title Loss- and Gain-of-Function Approaches Indicate a Dual Role Exerted by Regulatory T Cells in Pulmonary Paracoccidioidomycosis
title_full Loss- and Gain-of-Function Approaches Indicate a Dual Role Exerted by Regulatory T Cells in Pulmonary Paracoccidioidomycosis
title_fullStr Loss- and Gain-of-Function Approaches Indicate a Dual Role Exerted by Regulatory T Cells in Pulmonary Paracoccidioidomycosis
title_full_unstemmed Loss- and Gain-of-Function Approaches Indicate a Dual Role Exerted by Regulatory T Cells in Pulmonary Paracoccidioidomycosis
title_short Loss- and Gain-of-Function Approaches Indicate a Dual Role Exerted by Regulatory T Cells in Pulmonary Paracoccidioidomycosis
title_sort loss- and gain-of-function approaches indicate a dual role exerted by regulatory t cells in pulmonary paracoccidioidomycosis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4626087/
https://www.ncbi.nlm.nih.gov/pubmed/26512987
http://dx.doi.org/10.1371/journal.pntd.0004189
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