Cell-Intrinsic NF-κB Activation Is Critical for the Development of Natural Regulatory T Cells in Mice
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{"title"=>"Cell-intrinsic NF-κB activation is critical for the development of natural regulatory T cells in mice", "type"=>"journal", "authors"=>[{"first_name"=>"Eva", "last_name"=>"Gückel", "scopus_author_id"=>"16177513000"}, {"first_name"=>"Silke", "last_name"=>"Frey", "scopus_author_id"=>"43160977300"}, {"first_name"=>"Mario M.", "last_name"=>"Zaiss", "scopus_author_id"=>"23089495000"}, {"first_name"=>"Georg", "last_name"=>"Schett", "scopus_author_id"=>"7003435673"}, {"first_name"=>"Sankar", "last_name"=>"Ghosh", "scopus_author_id"=>"7404806316"}, {"first_name"=>"Reinhard E.", "last_name"=>"Voll", "scopus_author_id"=>"7006018669"}], "year"=>2011, "source"=>"PLoS ONE", "identifiers"=>{"pmid"=>"21625598", "issn"=>"19326203", "sgr"=>"79956210339", "pui"=>"361789483", "scopus"=>"2-s2.0-79956210339", "doi"=>"10.1371/journal.pone.0020003"}, "id"=>"ead25b1e-7b39-3b93-be7a-6e57f7a1a639", "abstract"=>"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.\\n\\nMETHODOLOGY/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.\\n\\nCONCLUSION/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.", "link"=>"http://www.mendeley.com/research/cellintrinsic-nf%CE%BAb-activation-critical-development-natural-regulatory-t-cells-mice-2", "reader_count"=>16, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>1, "Researcher"=>2, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>4, "Student > Postgraduate"=>2, "Student > Master"=>3, "Other"=>1, "Lecturer"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>1, "Researcher"=>2, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>4, "Student > Postgraduate"=>2, "Student > Master"=>3, "Other"=>1, "Lecturer"=>1}, "reader_count_by_subject_area"=>{"Agricultural and Biological Sciences"=>10, "Medicine and Dentistry"=>4, "Chemistry"=>2}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>4}, "Chemistry"=>{"Chemistry"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>10}}, "reader_count_by_country"=>{"United Kingdom"=>1, "Germany"=>1}, "group_count"=>0}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/388765", "https://ndownloader.figshare.com/files/388805", "https://ndownloader.figshare.com/files/388888", "https://ndownloader.figshare.com/files/388953", "https://ndownloader.figshare.com/files/388982", "https://ndownloader.figshare.com/files/389033", "https://ndownloader.figshare.com/files/389088"], "description"=>"<div><h3>Background</h3><p>Naturally occurring CD4<sup>+</sup>CD25<sup>+</sup>Foxp3<sup>+</sup> 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.</p> <h3>Methodology/Principal Findings</h3><p>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<sup>−</sup> 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.</p> <h3>Conclusion/Significance</h3><p>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.</p> </div>", "links"=>[], "tags"=>["cell-intrinsic", "activation", "cells", "mice"], "article_id"=>136756, "categories"=>["Immunology"], "users"=>["Eva Gückel", "Silke Frey", "Mario M. Zaiss", "Georg Schett", "Sankar Ghosh", "Reinhard E. Voll"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0020003.s001", "https://dx.doi.org/10.1371/journal.pone.0020003.s002", "https://dx.doi.org/10.1371/journal.pone.0020003.s003", "https://dx.doi.org/10.1371/journal.pone.0020003.s004", "https://dx.doi.org/10.1371/journal.pone.0020003.s005", "https://dx.doi.org/10.1371/journal.pone.0020003.s006", "https://dx.doi.org/10.1371/journal.pone.0020003.s007"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Cell_Intrinsic_NF_B_Activation_Is_Critical_for_the_Development_of_Natural_Regulatory_T_Cells_in_Mice/136756", "title"=>"Cell-Intrinsic NF-κB Activation Is Critical for the Development of Natural Regulatory T Cells in Mice", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2011-05-18 01:52:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/774988"], "description"=>"<p>Single-cell suspensions from thymus and spleen of wild-type (WT) and IκBα-“SuperRepressor” transgenic (IkB-SR Tg) mice were stained with CD4, CD8, CD25, and Foxp3 antibodies and analyzed by flow cytometry. (<b>A, C</b>) Representative dot plots from one of three independent experiments are shown. Expression profiles of CD4 versus CD8 (upper panels) and CD25 versus intracellular Foxp3 (gated on CD4 SP cells, lower panels) of thymocytes (<b>A</b>) and splenocytes (<b>C</b>) of WT and IkB-SR Tg mice. Numbers in the quadrants indicate the percentages of cells. (<b>B, D</b>) Percentages of CD25<sup>+</sup>Foxp3<sup>+</sup> Treg cells relative to CD4SP cells, as well as absolute numbers of Treg cells in the thymus (<b>B</b>) and spleen (<b>D</b>) of individual WT and IkB-SR Tg mice are displayed. Each symbol represents an individual mouse. Data were compiled from three independent experiments. In each experiment, organs from three mice per genotype were analyzed separately. Horizontal bars represent the mean. Mann-Whitney <i>U</i>-test was used for statistical analyses. *, p≤0.05; ***, p≤0.001; ns, not significant.</p>", "links"=>[], "tags"=>["numbers", "reduced", "tg"], "article_id"=>445356, "categories"=>["Immunology"], "users"=>["Eva Gückel", "Silke Frey", "Mario M. Zaiss", "Georg Schett", "Sankar Ghosh", "Reinhard E. Voll"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0020003.g001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Treg_cell_numbers_are_reduced_in_I_954_B_945_SR_Tg_mice_/445356", "title"=>"Treg cell numbers are reduced in IκBα-SR Tg mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-05-18 01:29:16"}
  • {"files"=>["https://ndownloader.figshare.com/files/775221"], "description"=>"<p>(<b>A</b>) Thymocytes from wild-type (WT) and IκBα-“SuperRepressor” transgenic (IkB-SR Tg) mice were either left untreated (−) or stimulated (+) with PMA and ionomycin for 24 h. The IL-2 concentrations in the supernatants were determined by ELISA. IL-2 secretion from unstimulated cells was below the detection limit. Mean values and SD were calculated from triplicates. Student's <i>t</i> test was used for statistical analyses. *, p≤0.05. (<b>B</b>, <b>C</b>, <b>D</b>) Wild-type and IkB-SR Tg mice were injected either with IL-2 or PBS every 8 h for 2 days and thymi were analyzed by flow cytometry. (<b>B</b>) Representative dot plots from one of three independent experiments are shown. Numbers in the quadrants represent the percentages of cells among CD4SP thymocytes from untreated (PBS) and IL-2 treated mice. (<b>C</b>) Percentages of CD25<sup>+</sup>Foxp3<sup>−</sup> cytokine-responsive Treg precursor cells among CD4SP thymocytes, as well as their absolute numbers in the thymus. (<b>D</b>) Percentages of CD25<sup>+</sup>Foxp3<sup>+</sup> mature Treg cells among CD4SP thymocytes, as well as their absolute numbers. (<b>B</b>, <b>C</b>, <b>D</b>) Data were compiled from two independent experiments with three mice per genotype and treatment in each experiment. Each symbol represents an individual mouse. Horizontal bars represent the mean. Mann-Whitney <i>U</i>-test was used for statistical analyses. *, p≤0.05; ns, not significant.</p>", "links"=>[], "tags"=>["treg", "numbers", "thymus", "tg"], "article_id"=>445590, "categories"=>["Immunology"], "users"=>["Eva Gückel", "Silke Frey", "Mario M. Zaiss", "Georg Schett", "Sankar Ghosh", "Reinhard E. Voll"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0020003.g002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_IL_2_can_only_partially_rescue_Treg_cell_numbers_in_the_thymus_of_I_954_B_945_SR_Tg_mice_/445590", "title"=>"IL-2 can only partially rescue Treg cell numbers in the thymus of IκBα-SR Tg mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-05-18 01:33:10"}
  • {"files"=>["https://ndownloader.figshare.com/files/775379"], "description"=>"<p>Mixed bone marrow chimeras were generated by either injecting equal numbers of CD45.1<sup>+</sup>C57BL/6 wild-type and CD45.2<sup>+</sup>IkB-SR Tg bone marrow cells (mixed chimera, n = 5) or just CD45.1<sup>+</sup>C57BL/6 wild-type bone marrow cells (WT chimera, n = 3) into lethally irradiated Rag1<sup>−/−</sup> recipient mice. Ten weeks later, Treg populations were examined in thymus, spleen and peripheral blood by flow cytometry. (<b>A</b>) Percentages of Treg cells in respect to CD45.1<sup>+</sup> or CD45.2<sup>+</sup> CD4SP cells as indicated in organs of mixed chimeras. Connected symbols indicate values from the same mouse. (<b>B, C</b>). Contributions of wild-type (CD45.1<sup>+</sup>) and IkB-SR Tg derived (CD45.2<sup>+</sup>) cells to the total Treg cell populations in thymus, spleen, and peripheral blood of mixed chimeras. Depicted are the mean values of percentages (<b>B</b>) as well as absolute cell numbers + SD (<b>C</b>) of contributing cells in the Treg population. Data are representative of two independent experiments with similar numbers of mice in each experimental group. Mann-Whitney <i>U</i>-test was used for statistical analyses. **, p≤0.01; ns, not significant.</p>", "links"=>[], "tags"=>["intrinsically", "impaired", "thymocytes", "overexpressing"], "article_id"=>445748, "categories"=>["Immunology"], "users"=>["Eva Gückel", "Silke Frey", "Mario M. Zaiss", "Georg Schett", "Sankar Ghosh", "Reinhard E. Voll"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0020003.g003"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Treg_cell_development_is_intrinsically_impaired_in_thymocytes_overexpressing_an_I_954_B_945_8220_SuperRepressor_8221_/445748", "title"=>"Treg cell development is intrinsically impaired in thymocytes overexpressing an IκBα-“SuperRepressor”.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-05-18 01:35:48"}
  • {"files"=>["https://ndownloader.figshare.com/files/775468"], "description"=>"<p>Wild-type mice either received the IKKβ-inhibitor AS602868 (30 mg/kg) or vehicle twice a day for 7 days and thymus and spleen were analyzed by flow cytometry. Representative dot plots from one of three independent experiments are shown (upper panel). Numbers in the quadrants represent the percentages of CD25<sup>+</sup>Foxp3<sup>+</sup> cells among CD4SP cells in thymus (<b>A</b>) and spleen (<b>B</b>) from untreated (Vehicle) and treated mice (AS602868). Percentages of CD25<sup>+</sup>Foxp3<sup>+</sup> Treg cells among CD4SP cells of individual mice are displayed (lower panel). Data are representative of three independent experiments with equal numbers of mice in each experimental group. Each symbol represents an individual mouse. Horizontal bars represent the mean. Mann-Whitney <i>U</i>-test was used for statistical analyses. *, p≤0.05; **, p≤0.01; ns, not significant.</p>", "links"=>[], "tags"=>["inhibition", "impairs", "thymic", "treg"], "article_id"=>445840, "categories"=>["Immunology"], "users"=>["Eva Gückel", "Silke Frey", "Mario M. Zaiss", "Georg Schett", "Sankar Ghosh", "Reinhard E. Voll"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0020003.g004"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Pharmacological_NF_954_B_inhibition_impairs_thymic_Treg_cell_development_/445840", "title"=>"Pharmacological NF-κB inhibition impairs thymic Treg cell development.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-05-18 01:37:20"}

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Relative Metric

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