The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Shane Crotty - One of the best experts on this subject based on the ideXlab platform.
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ezh2 programs t fh differentiation by integrating phosphorylation dependent activation of bcl6 and polycomb dependent repression of p19arf
Nature Communications, 2018Co-Authors: Zhouhao Zeng, Shane Crotty, Shaojun Xing, Jodi A Gullicksrud, Qiang Shan, Jinyong Choi, Vladimir P Badovinac, Weiqun PengAbstract:Ezh2 is an histone methyltransferase (HMT) that catalyzes H3K27me3 and functions in TH1, TH2, and Treg Cells primarily via HMT activity. Here we show that Ezh2 ablation impairs T follicular helper (Tfh) Cell differentiation and activation of the Tfh transcription program. In Tfh Cells, most Ezh2-occupied genomic sites, including the Bcl6 promoter, are associated with H3K27ac rather than H3K27me3. Mechanistically, Ezh2 is recruited by Tcf1 to directly activate Bcl6 transcription, with this function requiring Ezh2 phosphorylation at Ser21. Meanwhile, Ezh2 deploys H3K27me3 to repress Cdkn2a expression in Tfh Cells, where aberrantly upregulated p19Arf, a Cdkn2a protein product, triggers Tfh Cell apoptosis and antagonizes Bcl6 function via protein-protein interaction. Either forced expression of Bcl6 or genetic ablation of p19Arf in Ezh2-deficient Cells improves Tfh Cell differentiation and helper function. Thus, Ezh2 orchestrates Tfh-lineage specification and function maturation by integrating phosphorylation-dependent transcriptional activation and HMT-dependent gene repression.
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activin a programs the differentiation of human Tfh Cells
Nature Immunology, 2016Co-Authors: Michela Locci, Shane Crotty, Fortuna Arumemi, Zbigniew Mikulski, Carol Dahlberg, Andrew T MillerAbstract:Follicular helper T Cells (Tfh Cells) are CD4(+) T Cells specialized in helping B Cells and are associated both with protective antibody responses and autoimmune diseases. The promise of targeting Tfh Cells therapeutically has been limited by fragmentary understanding of extrinsic signals that regulate the differentiation of human Tfh Cells. A screen of a human protein library identified activin A as a potent regulator of Tfh Cell differentiation. Activin A orchestrated the expression of multiple genes associated with the Tfh program, independently or in concert with additional signals. Tfh Cell programming by activin A was antagonized by the cytokine IL-2. Activin A's ability to drive Tfh Cell differentiation in vitro was conserved in non-human primates but not in mice. Finally, activin-A-induced Tfh programming was dependent on signaling via SMAD2 and SMAD3 and was blocked by pharmacological inhibitors.
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cutting edge nfat transcription factors promote the generation of follicular helper t Cells in response to acute viral infection
Journal of Immunology, 2016Co-Authors: Gustavo J Martinez, Susan Togher, Renata M. Pereira, Shane Crotty, Joyce K Hu, Jordan S Crampton, Nicholas BildAbstract:Follicular CD4 + Th (Tfh) Cells provide B Cell help in germinal center reactions that support class switching, somatic hypermutation, and the generation of high-affinity Abs. In this article, we show that deficiency in NFAT1 and NFAT2 in CD4 + T Cells leads to impaired germinal center reactions upon viral infection because of reduced Tfh Cell differentiation and defective expression of proteins involved in T/B interactions and B Cell help, including ICOS, PD-1, and SLAM family receptors. Genome-wide chromatin immunoprecipitation data suggest that NFAT proteins likely directly participate in regulation of genes important for Tfh Cell differentiation and function. NFAT proteins are important TCR and Ca 2+ -dependent regulators of T Cell biology, and in this article we demonstrate a major positive role of NFAT family members in Tfh differentiation.
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BCL6 orchestrates Tfh Cell differentiation via multiple distinct mechanisms.
The Journal of experimental medicine, 2015Co-Authors: Katerina Hatzi, Ari Melnick, J. Philip Nance, Mark A. Kroenke, Marcella Bothwell, Elias K. Haddad, Shane CrottyAbstract:Follicular helper T Cells (Tfh Cells) are required for T Cell help to B Cells, and BCL6 is the defining transcription factor of Tfh Cells. However, the functions of BCL6 in Tfh Cells have largely remained unclear. Here we defined the BCL6 cistrome in primary human germinal center Tfh Cells to assess mechanisms of BCL6 regulation of CD4 T Cells, comparing and contrasting BCL6 function in T and B Cells. BCL6 primarily acts as a repressor in Tfh Cells, and BCL6 binding was associated with control of Tfh Cell migration and repression of alternative Cell fates. Interestingly, although some BCL6-bound genes possessed BCL6 DNA–binding motifs, many BCL6-bound loci were instead characterized by the presence of DNA motifs for AP1 or STAT. AP1 complexes are key positive downstream mediators of TCR signaling and external stimuli. We show that BCL6 can directly bind AP1, and BCL6 depends on AP1 for recruitment to BCL6-binding sites with AP1 motifs, suggesting that BCL6 subverts AP1 activity. These findings reveal that BCL6 has broad and multifaceted effects on Tfh biology and provide insight into how this master regulator mediates distinct Cell context–dependent phenotypes.
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t follicular helper Cell differentiation function and roles in disease
Immunity, 2014Co-Authors: Shane CrottyAbstract:Follicular helper T (Tfh) Cells are specialized providers of T Cell help to B Cells, and are essential for germinal center formation, affinity maturation, and the development of most high-affinity antibodies and memory B Cells. Tfh Cell differentiation is a multistage, multifactorial process involving B Cell lymphoma 6 (Bcl6) and other transcription factors. This article reviews understanding of Tfh Cell biology, including their differentiation, migration, transcriptional regulation, and B Cell help functions. Tfh Cells are critical components of many protective immune responses against pathogens. As such, there is strong interest in harnessing Tfh Cells to improve vaccination strategies. Tfh Cells also have roles in a range of other diseases, particularly autoimmune diseases. Overall, there have been dramatic advances in this young field, but there is much to be learned about Tfh Cell biology in the interest of applying that knowledge to biomedical needs.
Xiaohu Wang - One of the best experts on this subject based on the ideXlab platform.
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the transcription factor tox2 drives t follicular helper Cell development via regulating chromatin accessibility
Immunity, 2019Co-Authors: Xiaohu Wang, Wei Xu, Xiaohong Zhao, Xiaoshuang Wang, Han Feng, Chen DongAbstract:Summary T follicular helper (Tfh) Cells provide essential help to B Cells in germinal center (GC) reactions. Bcl6 is the obligatory lineage transcription factor in Tfh Cells. Here, we examined the molecular pathways that induce Bcl6 gene expression and underscore Bcl6-dependent function during Tfh Cell commitment. Integration of genome-wide Bcl6 occupancy in Tfh Cells and differential gene expression analyses suggested an important role for the transcription factor Tox2 in Tfh Cell differentiation. Ectopic expression of Tox2 was sufficient to drive Bcl6 expression and Tfh development. In genome-wide ChIP-seq analyses, Tox2-bound loci associated with Tfh Cell differentiation and function, including Bcl6. Tox2 binding was associated with increased chromatin accessibility at these sites, as measured by ATAC-seq. Tox2−/− mice exhibited defective Tfh differentiation, and inhibition of both Tox2 and the related transcription factor Tox abolished Tfh differentiation. Thus, a Tox2-Bcl6 axis establishes a transcriptional feed-forward loop that promotes the Tfh program.
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transcription factor achaete scute homologue 2 initiates follicular t helper Cell development
Nature, 2014Co-Authors: Xin Chen, Aibo Wang, Roza Nurieva, Xiaohu Wang, Bo Zhong, Ping Chen, Laurens G Van Der FlierAbstract:In immune responses, activated T Cells migrate to B-Cell follicles and develop into follicular T-helper (Tfh) Cells, a recently identified subset of CD4(+) T Cells specialized in providing help to B lymphocytes in the induction of germinal centres. Although Bcl6 has been shown to be essential in Tfh-Cell function, it may not regulate the initial migration of T Cells or the induction of the Tfh program, as exemplified by C-X-C chemokine receptor type 5 (CXCR5) upregulation. Here we show that expression of achaete-scute homologue 2 (Ascl2)--a basic helix-loop-helix (bHLH) transcription factor--is selectively upregulated in Tfh Cells. Ectopic expression of Ascl2 upregulates CXCR5 but not Bcl6, and downregulates C-C chemokine receptor 7 (CCR7) expression in T Cells in vitro, as well as accelerating T-Cell migration to the follicles and Tfh-Cell development in vivo in mice. Genome-wide analysis indicates that Ascl2 directly regulates Tfh-related genes whereas it inhibits expression of T-helper Cell 1 (TH1) and TH17 signature genes. Acute deletion of Ascl2, as well as blockade of its function with the Id3 protein in CD4(+) T Cells, results in impaired Tfh-Cell development and germinal centre response. Conversely, mutation of Id3, known to cause antibody-mediated autoimmunity, greatly enhances Tfh-Cell generation. Thus, Ascl2 directly initiates Tfh-Cell development.
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transcription factor achaete scute homologue 2 initiates follicular t helper Cell development
Nature, 2014Co-Authors: Xin Chen, Aibo Wang, Roza Nurieva, Xiaohu Wang, Bo Zhong, Ping Chen, Laurens G Van Der FlierAbstract:In immune responses, activated T Cells migrate to B-Cell follicles and develop into follicular T-helper (Tfh) Cells, a recently identified subset of CD4(+) T Cells specialized in providing help to B lymphocytes in the induction of germinal centres. Although Bcl6 has been shown to be essential in Tfh-Cell function, it may not regulate the initial migration of T Cells or the induction of the Tfh program, as exemplified by C-X-C chemokine receptor type 5 (CXCR5) upregulation. Here we show that expression of achaete-scute homologue 2 (Ascl2)--a basic helix-loop-helix (bHLH) transcription factor--is selectively upregulated in Tfh Cells. Ectopic expression of Ascl2 upregulates CXCR5 but not Bcl6, and downregulates C-C chemokine receptor 7 (CCR7) expression in T Cells in vitro, as well as accelerating T-Cell migration to the follicles and Tfh-Cell development in vivo in mice. Genome-wide analysis indicates that Ascl2 directly regulates Tfh-related genes whereas it inhibits expression of T-helper Cell 1 (TH1) and TH17 signature genes. Acute deletion of Ascl2, as well as blockade of its function with the Id3 protein in CD4(+) T Cells, results in impaired Tfh-Cell development and germinal centre response. Conversely, mutation of Id3, known to cause antibody-mediated autoimmunity, greatly enhances Tfh-Cell generation. Thus, Ascl2 directly initiates Tfh-Cell development.
Laurens G Van Der Flier - One of the best experts on this subject based on the ideXlab platform.
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transcription factor achaete scute homologue 2 initiates follicular t helper Cell development
Nature, 2014Co-Authors: Xin Chen, Aibo Wang, Roza Nurieva, Xiaohu Wang, Bo Zhong, Ping Chen, Laurens G Van Der FlierAbstract:In immune responses, activated T Cells migrate to B-Cell follicles and develop into follicular T-helper (Tfh) Cells, a recently identified subset of CD4(+) T Cells specialized in providing help to B lymphocytes in the induction of germinal centres. Although Bcl6 has been shown to be essential in Tfh-Cell function, it may not regulate the initial migration of T Cells or the induction of the Tfh program, as exemplified by C-X-C chemokine receptor type 5 (CXCR5) upregulation. Here we show that expression of achaete-scute homologue 2 (Ascl2)--a basic helix-loop-helix (bHLH) transcription factor--is selectively upregulated in Tfh Cells. Ectopic expression of Ascl2 upregulates CXCR5 but not Bcl6, and downregulates C-C chemokine receptor 7 (CCR7) expression in T Cells in vitro, as well as accelerating T-Cell migration to the follicles and Tfh-Cell development in vivo in mice. Genome-wide analysis indicates that Ascl2 directly regulates Tfh-related genes whereas it inhibits expression of T-helper Cell 1 (TH1) and TH17 signature genes. Acute deletion of Ascl2, as well as blockade of its function with the Id3 protein in CD4(+) T Cells, results in impaired Tfh-Cell development and germinal centre response. Conversely, mutation of Id3, known to cause antibody-mediated autoimmunity, greatly enhances Tfh-Cell generation. Thus, Ascl2 directly initiates Tfh-Cell development.
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transcription factor achaete scute homologue 2 initiates follicular t helper Cell development
Nature, 2014Co-Authors: Xin Chen, Aibo Wang, Roza Nurieva, Xiaohu Wang, Bo Zhong, Ping Chen, Laurens G Van Der FlierAbstract:In immune responses, activated T Cells migrate to B-Cell follicles and develop into follicular T-helper (Tfh) Cells, a recently identified subset of CD4(+) T Cells specialized in providing help to B lymphocytes in the induction of germinal centres. Although Bcl6 has been shown to be essential in Tfh-Cell function, it may not regulate the initial migration of T Cells or the induction of the Tfh program, as exemplified by C-X-C chemokine receptor type 5 (CXCR5) upregulation. Here we show that expression of achaete-scute homologue 2 (Ascl2)--a basic helix-loop-helix (bHLH) transcription factor--is selectively upregulated in Tfh Cells. Ectopic expression of Ascl2 upregulates CXCR5 but not Bcl6, and downregulates C-C chemokine receptor 7 (CCR7) expression in T Cells in vitro, as well as accelerating T-Cell migration to the follicles and Tfh-Cell development in vivo in mice. Genome-wide analysis indicates that Ascl2 directly regulates Tfh-related genes whereas it inhibits expression of T-helper Cell 1 (TH1) and TH17 signature genes. Acute deletion of Ascl2, as well as blockade of its function with the Id3 protein in CD4(+) T Cells, results in impaired Tfh-Cell development and germinal centre response. Conversely, mutation of Id3, known to cause antibody-mediated autoimmunity, greatly enhances Tfh-Cell generation. Thus, Ascl2 directly initiates Tfh-Cell development.
Xin Chen - One of the best experts on this subject based on the ideXlab platform.
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transcription factor achaete scute homologue 2 initiates follicular t helper Cell development
Nature, 2014Co-Authors: Xin Chen, Aibo Wang, Roza Nurieva, Xiaohu Wang, Bo Zhong, Ping Chen, Laurens G Van Der FlierAbstract:In immune responses, activated T Cells migrate to B-Cell follicles and develop into follicular T-helper (Tfh) Cells, a recently identified subset of CD4(+) T Cells specialized in providing help to B lymphocytes in the induction of germinal centres. Although Bcl6 has been shown to be essential in Tfh-Cell function, it may not regulate the initial migration of T Cells or the induction of the Tfh program, as exemplified by C-X-C chemokine receptor type 5 (CXCR5) upregulation. Here we show that expression of achaete-scute homologue 2 (Ascl2)--a basic helix-loop-helix (bHLH) transcription factor--is selectively upregulated in Tfh Cells. Ectopic expression of Ascl2 upregulates CXCR5 but not Bcl6, and downregulates C-C chemokine receptor 7 (CCR7) expression in T Cells in vitro, as well as accelerating T-Cell migration to the follicles and Tfh-Cell development in vivo in mice. Genome-wide analysis indicates that Ascl2 directly regulates Tfh-related genes whereas it inhibits expression of T-helper Cell 1 (TH1) and TH17 signature genes. Acute deletion of Ascl2, as well as blockade of its function with the Id3 protein in CD4(+) T Cells, results in impaired Tfh-Cell development and germinal centre response. Conversely, mutation of Id3, known to cause antibody-mediated autoimmunity, greatly enhances Tfh-Cell generation. Thus, Ascl2 directly initiates Tfh-Cell development.
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transcription factor achaete scute homologue 2 initiates follicular t helper Cell development
Nature, 2014Co-Authors: Xin Chen, Aibo Wang, Roza Nurieva, Xiaohu Wang, Bo Zhong, Ping Chen, Laurens G Van Der FlierAbstract:In immune responses, activated T Cells migrate to B-Cell follicles and develop into follicular T-helper (Tfh) Cells, a recently identified subset of CD4(+) T Cells specialized in providing help to B lymphocytes in the induction of germinal centres. Although Bcl6 has been shown to be essential in Tfh-Cell function, it may not regulate the initial migration of T Cells or the induction of the Tfh program, as exemplified by C-X-C chemokine receptor type 5 (CXCR5) upregulation. Here we show that expression of achaete-scute homologue 2 (Ascl2)--a basic helix-loop-helix (bHLH) transcription factor--is selectively upregulated in Tfh Cells. Ectopic expression of Ascl2 upregulates CXCR5 but not Bcl6, and downregulates C-C chemokine receptor 7 (CCR7) expression in T Cells in vitro, as well as accelerating T-Cell migration to the follicles and Tfh-Cell development in vivo in mice. Genome-wide analysis indicates that Ascl2 directly regulates Tfh-related genes whereas it inhibits expression of T-helper Cell 1 (TH1) and TH17 signature genes. Acute deletion of Ascl2, as well as blockade of its function with the Id3 protein in CD4(+) T Cells, results in impaired Tfh-Cell development and germinal centre response. Conversely, mutation of Id3, known to cause antibody-mediated autoimmunity, greatly enhances Tfh-Cell generation. Thus, Ascl2 directly initiates Tfh-Cell development.
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Tfh Cell differentiation and their function in promoting b Cell responses
Advances in Experimental Medicine and Biology, 2014Co-Authors: Xin Chen, Coco Chu, Dan Liu, Yifeng Wang, Hu Yan, Jiacong YanAbstract:Follicular helper T Cells (Tfh) are a newly defined helper T-Cell subset that is specialized in facilitating B-Cell responses. These Cells have a unique tissue localization pattern and a distinct transcriptional program suited for the B-Cell helper function. Co-opting of the follicular program affords regulatory T Cells, NK T Cells, and γδ T Cells with opportunities to participate in the regulation of humoral immunity. Abnormal Tfh development and function can lead to immunodeficiencies, autoimmune inflammation, and tumors. Detailed understanding of Tfh Cell differentiation and function in animal models and the human system promises better strategies toward vaccine development and therapies for inflammatory diseases.
Aibo Wang - One of the best experts on this subject based on the ideXlab platform.
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transcription factor achaete scute homologue 2 initiates follicular t helper Cell development
Nature, 2014Co-Authors: Xin Chen, Aibo Wang, Roza Nurieva, Xiaohu Wang, Bo Zhong, Ping Chen, Laurens G Van Der FlierAbstract:In immune responses, activated T Cells migrate to B-Cell follicles and develop into follicular T-helper (Tfh) Cells, a recently identified subset of CD4(+) T Cells specialized in providing help to B lymphocytes in the induction of germinal centres. Although Bcl6 has been shown to be essential in Tfh-Cell function, it may not regulate the initial migration of T Cells or the induction of the Tfh program, as exemplified by C-X-C chemokine receptor type 5 (CXCR5) upregulation. Here we show that expression of achaete-scute homologue 2 (Ascl2)--a basic helix-loop-helix (bHLH) transcription factor--is selectively upregulated in Tfh Cells. Ectopic expression of Ascl2 upregulates CXCR5 but not Bcl6, and downregulates C-C chemokine receptor 7 (CCR7) expression in T Cells in vitro, as well as accelerating T-Cell migration to the follicles and Tfh-Cell development in vivo in mice. Genome-wide analysis indicates that Ascl2 directly regulates Tfh-related genes whereas it inhibits expression of T-helper Cell 1 (TH1) and TH17 signature genes. Acute deletion of Ascl2, as well as blockade of its function with the Id3 protein in CD4(+) T Cells, results in impaired Tfh-Cell development and germinal centre response. Conversely, mutation of Id3, known to cause antibody-mediated autoimmunity, greatly enhances Tfh-Cell generation. Thus, Ascl2 directly initiates Tfh-Cell development.
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transcription factor achaete scute homologue 2 initiates follicular t helper Cell development
Nature, 2014Co-Authors: Xin Chen, Aibo Wang, Roza Nurieva, Xiaohu Wang, Bo Zhong, Ping Chen, Laurens G Van Der FlierAbstract:In immune responses, activated T Cells migrate to B-Cell follicles and develop into follicular T-helper (Tfh) Cells, a recently identified subset of CD4(+) T Cells specialized in providing help to B lymphocytes in the induction of germinal centres. Although Bcl6 has been shown to be essential in Tfh-Cell function, it may not regulate the initial migration of T Cells or the induction of the Tfh program, as exemplified by C-X-C chemokine receptor type 5 (CXCR5) upregulation. Here we show that expression of achaete-scute homologue 2 (Ascl2)--a basic helix-loop-helix (bHLH) transcription factor--is selectively upregulated in Tfh Cells. Ectopic expression of Ascl2 upregulates CXCR5 but not Bcl6, and downregulates C-C chemokine receptor 7 (CCR7) expression in T Cells in vitro, as well as accelerating T-Cell migration to the follicles and Tfh-Cell development in vivo in mice. Genome-wide analysis indicates that Ascl2 directly regulates Tfh-related genes whereas it inhibits expression of T-helper Cell 1 (TH1) and TH17 signature genes. Acute deletion of Ascl2, as well as blockade of its function with the Id3 protein in CD4(+) T Cells, results in impaired Tfh-Cell development and germinal centre response. Conversely, mutation of Id3, known to cause antibody-mediated autoimmunity, greatly enhances Tfh-Cell generation. Thus, Ascl2 directly initiates Tfh-Cell development.
