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Cell-Intrinsic NF-κB Activation Is Critical for the Development of Natural Regulatory T Cells in Mice

BACKGROUND: Naturally occurring CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells develop in the thymus and represent a mature T cell subpopulation critically involved in maintaining peripheral tolerance. The differentiation of Treg cells in the thymus requires T cell receptor (TCR)/CD28 stimulation a...

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Autores principales: Gückel, Eva, Frey, Silke, Zaiss, Mario M., Schett, Georg, Ghosh, Sankar, Voll, Reinhard E.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3097234/
https://www.ncbi.nlm.nih.gov/pubmed/21625598
http://dx.doi.org/10.1371/journal.pone.0020003
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author Gückel, Eva
Frey, Silke
Zaiss, Mario M.
Schett, Georg
Ghosh, Sankar
Voll, Reinhard E.
author_facet Gückel, Eva
Frey, Silke
Zaiss, Mario M.
Schett, Georg
Ghosh, Sankar
Voll, Reinhard E.
author_sort Gückel, Eva
collection PubMed
description BACKGROUND: Naturally occurring CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells develop in the thymus and represent a mature T cell subpopulation critically involved in maintaining peripheral tolerance. The differentiation of Treg cells in the thymus requires T cell receptor (TCR)/CD28 stimulation along with cytokine-promoted Foxp3 induction. TCR-mediated nuclear factor kappa B (NF-κB) activation seems to be involved in differentiation of Treg cells because deletion of components of the NF-κB signaling pathway, as well as of NF-κB transcription factors, leads to markedly decreased Treg cell numbers in thymus and periphery. METHODOLOGY/PRINCIPAL FINDINGS: To investigate if Treg cell-intrinsic NF-κB activation is required for thymic development and peripheral homeostasis of Treg cells we used transgenic (Tg) mice with thymocyte-specific expression of a stable IκBα mutant to inhibit NF-κB activation solely within the T cell lineage. Here we show that Treg cell-intrinsic NF-κB activation is important for the generation of cytokine-responsive Foxp3(−) thymic Treg precursors and their further differentiation into mature Treg cells. Treg cell development could neither be completely rescued by the addition of exogenous Interleukin 2 (IL-2) nor by the presence of wild-type derived cells in adoptive transfer experiments. However, peripheral NF-κB activation appears to be required for IL-2 production by conventional T cells, thereby participating in Treg cell homeostasis. Moreover, pharmacological NF-κB inhibition via the IκB kinase β (IKKβ) inhibitor AS602868 led to markedly diminished thymic and peripheral Treg cell frequencies. CONCLUSION/SIGNIFICANCE: Our results indicate that Treg cell-intrinsic NF-κB activation is essential for thymic Treg cell differentiation, and further suggest pharmacological NF-κB inhibition as a potential therapeutic approach for manipulating this process.
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spelling pubmed-30972342011-05-27 Cell-Intrinsic NF-κB Activation Is Critical for the Development of Natural Regulatory T Cells in Mice Gückel, Eva Frey, Silke Zaiss, Mario M. Schett, Georg Ghosh, Sankar Voll, Reinhard E. PLoS One Research Article BACKGROUND: Naturally occurring CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells develop in the thymus and represent a mature T cell subpopulation critically involved in maintaining peripheral tolerance. The differentiation of Treg cells in the thymus requires T cell receptor (TCR)/CD28 stimulation along with cytokine-promoted Foxp3 induction. TCR-mediated nuclear factor kappa B (NF-κB) activation seems to be involved in differentiation of Treg cells because deletion of components of the NF-κB signaling pathway, as well as of NF-κB transcription factors, leads to markedly decreased Treg cell numbers in thymus and periphery. METHODOLOGY/PRINCIPAL FINDINGS: To investigate if Treg cell-intrinsic NF-κB activation is required for thymic development and peripheral homeostasis of Treg cells we used transgenic (Tg) mice with thymocyte-specific expression of a stable IκBα mutant to inhibit NF-κB activation solely within the T cell lineage. Here we show that Treg cell-intrinsic NF-κB activation is important for the generation of cytokine-responsive Foxp3(−) thymic Treg precursors and their further differentiation into mature Treg cells. Treg cell development could neither be completely rescued by the addition of exogenous Interleukin 2 (IL-2) nor by the presence of wild-type derived cells in adoptive transfer experiments. However, peripheral NF-κB activation appears to be required for IL-2 production by conventional T cells, thereby participating in Treg cell homeostasis. Moreover, pharmacological NF-κB inhibition via the IκB kinase β (IKKβ) inhibitor AS602868 led to markedly diminished thymic and peripheral Treg cell frequencies. CONCLUSION/SIGNIFICANCE: Our results indicate that Treg cell-intrinsic NF-κB activation is essential for thymic Treg cell differentiation, and further suggest pharmacological NF-κB inhibition as a potential therapeutic approach for manipulating this process. Public Library of Science 2011-05-18 /pmc/articles/PMC3097234/ /pubmed/21625598 http://dx.doi.org/10.1371/journal.pone.0020003 Text en Gückel 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
Gückel, Eva
Frey, Silke
Zaiss, Mario M.
Schett, Georg
Ghosh, Sankar
Voll, Reinhard E.
Cell-Intrinsic NF-κB Activation Is Critical for the Development of Natural Regulatory T Cells in Mice
title Cell-Intrinsic NF-κB Activation Is Critical for the Development of Natural Regulatory T Cells in Mice
title_full Cell-Intrinsic NF-κB Activation Is Critical for the Development of Natural Regulatory T Cells in Mice
title_fullStr Cell-Intrinsic NF-κB Activation Is Critical for the Development of Natural Regulatory T Cells in Mice
title_full_unstemmed Cell-Intrinsic NF-κB Activation Is Critical for the Development of Natural Regulatory T Cells in Mice
title_short Cell-Intrinsic NF-κB Activation Is Critical for the Development of Natural Regulatory T Cells in Mice
title_sort cell-intrinsic nf-κb activation is critical for the development of natural regulatory t cells in mice
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3097234/
https://www.ncbi.nlm.nih.gov/pubmed/21625598
http://dx.doi.org/10.1371/journal.pone.0020003
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