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  1. Article ; Online: Nuclear receptor LXRβ controls fitness and functionality of activated T cells.

    Michaels, Anthony J / Campbell, Clarissa / Bou-Puerto, Regina / Rudensky, Alexander Y

    The Journal of experimental medicine

    2021  Volume 218, Issue 4

    Abstract: T cells increase cholesterol biosynthesis upon activation to generate substrates for cellular growth and proliferation. The ubiquitously expressed liver X receptor β (LXRβ) encoded by the Nr1h2 gene is a critical regulator of cholesterol homeostasis in ... ...

    Abstract T cells increase cholesterol biosynthesis upon activation to generate substrates for cellular growth and proliferation. The ubiquitously expressed liver X receptor β (LXRβ) encoded by the Nr1h2 gene is a critical regulator of cholesterol homeostasis in mammalian cells; however, its cell-intrinsic role in T cell biology remains poorly understood. We report that ablation of LXRβ in T cells leads to spontaneous T cell activation and T lymphocytopenia. Unexpectedly, analysis of mixed bone marrow chimeric mice revealed a cell-autonomous survival defect that reduced the fitness of LXRβ-deficient effector T cells, suggesting that the heightened immune activation in mice harboring LXRβ-deficient T cells was due to impaired regulatory T (T reg) cell functionality. Indeed, we found that single-copy deletion of Nr1h2 in T reg cells disrupted activated T reg cell metabolism and fitness and resulted in early-onset fatal autoimmune disease. Our study demonstrated an indispensable requirement for T reg cell-intrinsic LXRβ function in immune homeostasis and provides a basis for immunological therapies through targeting of this receptor.
    MeSH term(s) Animals ; Autoimmune Diseases/genetics ; Autoimmune Diseases/immunology ; Cells, Cultured ; Cholesterol/metabolism ; Female ; Forkhead Transcription Factors/genetics ; Homeostasis/genetics ; Homeostasis/immunology ; Liver X Receptors/genetics ; Liver X Receptors/physiology ; Lymphocyte Activation/genetics ; Male ; Mice ; Mice, Inbred C57BL ; Radiation Chimera/immunology ; Signal Transduction/genetics ; T-Lymphocytes, Regulatory/immunology ; T-Lymphocytes, Regulatory/metabolism ; T-Lymphocytopenia, Idiopathic CD4-Positive/genetics ; T-Lymphocytopenia, Idiopathic CD4-Positive/immunology
    Chemical Substances Forkhead Transcription Factors ; Foxp3 protein, mouse ; Liver X Receptors ; Nr1h2 protein, mouse ; Cholesterol (97C5T2UQ7J)
    Language English
    Publishing date 2021-02-12
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 218343-2
    ISSN 1540-9538 ; 0022-1007
    ISSN (online) 1540-9538
    ISSN 0022-1007
    DOI 10.1084/jem.20201311
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Ua VI Zs.107: Show issues Location:
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  2. Article ; Online: CRISPR-Mediated Editing of the B Cell Receptor in Primary Human B Cells.

    Greiner, Vera / Bou Puerto, Regina / Liu, Suying / Herbel, Christoph / Carmona, Ellese M / Goldberg, Michael S

    iScience

    2019  Volume 12, Page(s) 369–378

    Abstract: Vaccination approaches have generally focused on the antigen rather than the resultant antibodies generated, which differ greatly in quality and function between individuals. The ability to replace the variable regions of the native B cell receptor (BCR) ...

    Abstract Vaccination approaches have generally focused on the antigen rather than the resultant antibodies generated, which differ greatly in quality and function between individuals. The ability to replace the variable regions of the native B cell receptor (BCR) heavy and light chain loci with defined recombined sequences of a preferred monoclonal antibody could enable curative adoptive cell transfer. We report CRISPR-mediated homologous recombination (HR) into the BCR of primary human B cells. Ribonucleoprotein delivery enabled editing at the model CXCR4 locus, as demonstrated by T7E1 assay, flow cytometry, and TIDE analysis. Insertion via HR was confirmed by sequencing, cross-boundary PCR, and restriction digest. Optimized conditions were used to achieve HR at the BCR variable heavy and light chains. Insertion was confirmed at the DNA level, and transgene expression from the native BCR promoters was observed. Reprogramming the specificity of antibodies in the genomes of B cells could have clinical importance.
    Language English
    Publishing date 2019-02-01
    Publishing country United States
    Document type Journal Article
    ISSN 2589-0042
    ISSN (online) 2589-0042
    DOI 10.1016/j.isci.2019.01.032
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Cell-intrinsic adrenergic signaling controls the adaptive NK cell response to viral infection.

    Diaz-Salazar, Carlos / Bou-Puerto, Regina / Mujal, Adriana M / Lau, Colleen M / von Hoesslin, Madlaina / Zehn, Dietmar / Sun, Joseph C

    The Journal of experimental medicine

    2020  Volume 217, Issue 4

    Abstract: Natural killer (NK) cells are innate lymphocytes that exhibit adaptive features, such as clonal expansion and memory, during viral infection. Although activating receptor engagement and proinflammatory cytokines are required to drive NK cell clonal ... ...

    Abstract Natural killer (NK) cells are innate lymphocytes that exhibit adaptive features, such as clonal expansion and memory, during viral infection. Although activating receptor engagement and proinflammatory cytokines are required to drive NK cell clonal expansion, additional stimulatory signals controlling their proliferation remain to be discovered. Here, we describe one such signal that is provided by the adrenergic nervous system, and demonstrate that cell-intrinsic adrenergic signaling is required for optimal adaptive NK cell responses. Early during mouse cytomegalovirus (MCMV) infection, NK cells up-regulated Adrb2 (which encodes the β2-adrenergic receptor), a process dependent on IL-12 and STAT4 signaling. NK cell-specific deletion of Adrb2 resulted in impaired NK cell expansion and memory during MCMV challenge, in part due to a diminished proliferative capacity. As a result, NK cell-intrinsic adrenergic signaling was required for protection against MCMV. Taken together, we propose a novel role for the adrenergic nervous system in regulating circulating lymphocyte responses to viral infection.
    MeSH term(s) Adrenergic Neurons/immunology ; Animals ; Cell Proliferation/physiology ; Cytokines/immunology ; Cytomegalovirus Infections/immunology ; Immunologic Memory/immunology ; Interleukin-12/immunology ; Killer Cells, Natural/immunology ; Lymphocyte Activation/immunology ; Mice ; Mice, Inbred C57BL ; Muromegalovirus/immunology ; Receptors, Adrenergic, beta-2/immunology ; STAT4 Transcription Factor/immunology ; Signal Transduction/immunology ; Up-Regulation/immunology
    Chemical Substances Cytokines ; Receptors, Adrenergic, beta-2 ; STAT4 Transcription Factor ; Interleukin-12 (187348-17-0)
    Language English
    Publishing date 2020-02-11
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 218343-2
    ISSN 1540-9538 ; 0022-1007
    ISSN (online) 1540-9538
    ISSN 0022-1007
    DOI 10.1084/jem.20190549
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Ua VI Zs.107: Show issues Location:
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  4. Article ; Online: Assembly of a spatial circuit of T-bet-expressing T and B lymphocytes is required for antiviral humoral immunity.

    Mendoza, Alejandra / Yewdell, William T / Hoyos, Beatrice / Schizas, Michail / Bou-Puerto, Regina / Michaels, Anthony J / Brown, Chrysothemis C / Chaudhuri, Jayanta / Rudensky, Alexander Y

    Science immunology

    2021  Volume 6, Issue 60

    Abstract: Effective antiviral immunity requires generation of T and B lymphocytes expressing the transcription factor T-bet, a regulator of type 1 inflammatory responses. Using T-bet expression as an endogenous marker for cells participating in a type 1 response, ... ...

    Abstract Effective antiviral immunity requires generation of T and B lymphocytes expressing the transcription factor T-bet, a regulator of type 1 inflammatory responses. Using T-bet expression as an endogenous marker for cells participating in a type 1 response, we report coordinated interactions of T-bet-expressing T and B lymphocytes on the basis of their dynamic colocalization at the T cell zone and B follicle boundary (T-B boundary) and germinal centers (GCs) during lung influenza infection. We demonstrate that the assembly of this circuit takes place in distinct anatomical niches within the draining lymph node, guided by CXCR3 that enables positioning of T
    MeSH term(s) Animals ; B-Lymphocytes/immunology ; B-Lymphocytes/metabolism ; Cell Communication/immunology ; Disease Models, Animal ; Female ; Germinal Center/cytology ; Germinal Center/metabolism ; Humans ; Immunity, Humoral ; Immunoglobulin Class Switching ; Influenza A virus/immunology ; Influenza, Human/immunology ; Influenza, Human/pathology ; Influenza, Human/virology ; Interferon-gamma/genetics ; Interferon-gamma/metabolism ; Lung/immunology ; Lung/pathology ; Lung/virology ; Male ; Mice ; Mice, Transgenic ; Nippostrongylus/immunology ; Rats ; Receptors, CXCR3/metabolism ; Strongylida Infections/immunology ; Strongylida Infections/parasitology ; T-Box Domain Proteins/genetics ; T-Box Domain Proteins/metabolism ; T-Lymphocyte Subsets/immunology ; T-Lymphocyte Subsets/metabolism ; Th1 Cells/immunology ; Th1 Cells/metabolism
    Chemical Substances Cxcr3 protein, mouse ; IFNG protein, mouse ; Receptors, CXCR3 ; T-Box Domain Proteins ; T-box transcription factor TBX21 ; Interferon-gamma (82115-62-6)
    Language English
    Publishing date 2021-06-09
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 2470-9468
    ISSN (online) 2470-9468
    DOI 10.1126/sciimmunol.abi4710
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Regulatory T cells function in established systemic inflammation and reverse fatal autoimmunity.

    Hu, Wei / Wang, Zhong-Min / Feng, Yongqiang / Schizas, Michail / Hoyos, Beatrice E / van der Veeken, Joris / Verter, Jacob G / Bou-Puerto, Regina / Rudensky, Alexander Y

    Nature immunology

    2021  Volume 22, Issue 9, Page(s) 1163–1174

    Abstract: The immunosuppressive function of regulatory T ( ... ...

    Abstract The immunosuppressive function of regulatory T (T
    MeSH term(s) Animals ; Autoimmune Diseases/immunology ; Autoimmunity/genetics ; Autoimmunity/immunology ; Cell Differentiation/immunology ; Female ; Forkhead Transcription Factors/genetics ; Forkhead Transcription Factors/metabolism ; Gene Expression Regulation/genetics ; Homeostasis/immunology ; Inflammation Mediators/metabolism ; Lymphocyte Activation/immunology ; Male ; Mice ; Mice, Inbred C57BL ; Systemic Inflammatory Response Syndrome/immunology ; Systemic Inflammatory Response Syndrome/pathology ; T-Lymphocytes, Regulatory/immunology
    Chemical Substances Forkhead Transcription Factors ; Foxp3 protein, mouse ; Inflammation Mediators
    Language English
    Publishing date 2021-08-23
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2016987-5
    ISSN 1529-2916 ; 1529-2908
    ISSN (online) 1529-2916
    ISSN 1529-2908
    DOI 10.1038/s41590-021-01001-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 5294: Show issues Location:
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  6. Article ; Online: The Transcription Factor Foxp3 Shapes Regulatory T Cell Identity by Tuning the Activity of trans-Acting Intermediaries.

    van der Veeken, Joris / Glasner, Ariella / Zhong, Yi / Hu, Wei / Wang, Zhong-Min / Bou-Puerto, Regina / Charbonnier, Louis-Marie / Chatila, Talal A / Leslie, Christina S / Rudensky, Alexander Y

    Immunity

    2020  Volume 53, Issue 5, Page(s) 971–984.e5

    Abstract: Regulatory T (Treg) cell identity is defined by the lineage-specifying transcription factor (TF) Foxp3. Here we examined mechanisms of Foxp3 function by leveraging naturally occurring genetic variation in wild-derived inbred mice, which enables the ... ...

    Abstract Regulatory T (Treg) cell identity is defined by the lineage-specifying transcription factor (TF) Foxp3. Here we examined mechanisms of Foxp3 function by leveraging naturally occurring genetic variation in wild-derived inbred mice, which enables the identification of DNA sequence motifs driving epigenetic features. Chromatin accessibility, TF binding, and gene expression patterns in resting and activated subsets of Treg cells, conventional CD4 T cells, and cells expressing a Foxp3 reporter null allele revealed that the majority of Foxp3-dependent changes occurred at sites not bound by Foxp3. Chromatin accessibility of these indirect Foxp3 targets depended on the presence of DNA binding motifs for other TFs, including TCF1. Foxp3 expression correlated with decreased TCF1 and reduced accessibility of TCF1-bound chromatin regions. Deleting one copy of the Tcf7 gene recapitulated Foxp3-dependent negative regulation of chromatin accessibility. Thus, Foxp3 defines Treg cell identity in a largely indirect manner by fine-tuning the activity of other major chromatin remodeling TFs such as TCF1.
    MeSH term(s) Animals ; Autoimmune Diseases/etiology ; Autoimmune Diseases/metabolism ; Autoimmune Diseases/pathology ; Autoimmunity/genetics ; Binding Sites ; Chromatin Assembly and Disassembly ; Disease Models, Animal ; Epigenesis, Genetic ; Female ; Forkhead Transcription Factors/genetics ; Forkhead Transcription Factors/metabolism ; Gene Expression Regulation ; Immunohistochemistry ; Male ; Mice ; Nucleotide Motifs ; Organ Specificity/genetics ; Organ Specificity/immunology ; Protein Binding ; T-Lymphocytes, Regulatory/immunology ; T-Lymphocytes, Regulatory/metabolism ; Trans-Activators/metabolism
    Chemical Substances Forkhead Transcription Factors ; Foxp3 protein, mouse ; Trans-Activators
    Language English
    Publishing date 2020-11-10
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1217235-2
    ISSN 1097-4180 ; 1074-7613
    ISSN (online) 1097-4180
    ISSN 1074-7613
    DOI 10.1016/j.immuni.2020.10.010
    Database MEDical Literature Analysis and Retrieval System OnLINE

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