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  • 1
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    Clonal selection in the germinal centre by regulated proliferation and hypermutation (2014)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2014-05-09
    Description: During immune responses, B lymphocytes clonally expand and undergo secondary diversification of their immunoglobulin genes in germinal centres (GCs). High-affinity B cells are expanded through iterative interzonal cycles of division and hypermutation in the GC dark zone followed by migration to the GC light zone, where they are selected on the basis of affinity to return to the dark zone. Here we combine a transgenic strategy to measure cell division and a photoactivatable fluorescent reporter to examine whether the extent of clonal expansion and hypermutation are regulated during interzonal GC cycles. We find that both cell division and hypermutation are directly proportional to the amount of antigen captured and presented by GC B cells to follicular helper T cells in the light zone. Our data explain how GC B cells with the highest affinity for antigen are selectively expanded and diversified.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4271732/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4271732/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gitlin, Alexander D -- Shulman, Ziv -- Nussenzweig, Michel C -- 1UM1 AI100663-01/AI/NIAID NIH HHS/ -- AI037526-19/AI/NIAID NIH HHS/ -- AI072529-06/AI/NIAID NIH HHS/ -- R01 AI037526/AI/NIAID NIH HHS/ -- R01 AI072529/AI/NIAID NIH HHS/ -- T32GM07739/GM/NIGMS NIH HHS/ -- UM1 AI100663/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 May 29;509(7502):637-40. doi: 10.1038/nature13300. Epub 2014 May 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Immunology, The Rockefeller University, New York, New York 10065, USA. ; 1] Laboratory of Molecular Immunology, The Rockefeller University, New York, New York 10065, USA [2] Howard Hughes Medical Institute, The Rockefeller University, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24805232" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antibody Affinity/immunology ; Antigen Presentation/immunology ; Antigens/immunology ; B-Lymphocytes/*cytology/immunology/*metabolism ; Cell Movement ; Cell Proliferation ; *Clonal Selection, Antigen-Mediated/immunology ; Clone Cells/cytology/immunology/metabolism ; Genes, Reporter/genetics ; Germinal Center/*cytology/*immunology ; Male ; Mice ; S Phase ; Somatic Hypermutation, Immunoglobulin/*genetics ; T-Lymphocytes, Helper-Inducer/cytology/immunology ; Time Factors
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    T follicular helper cell dynamics in germinal centers (2013)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2013-07-28
    Description: T follicular helper (T(FH)) cells are a specialized subset of effector T cells that provide help to and thereby select high-affinity B cells in germinal centers (GCs). To examine the dynamic behavior of T(FH) cells in GCs in mice, we used two-photon microscopy in combination with a photoactivatable fluorescent reporter. Unlike GC B cells, which are clonally restricted, T(FH) cells distributed among all GCs in lymph nodes and continually emigrated into the follicle and neighboring GCs. Moreover, newly activated T(FH) cells invaded preexisting GCs, where they contributed to B cell selection and plasmablast differentiation. Our data suggest that the dynamic exchange of T(FH) cells between GCs ensures maximal diversification of T cell help and that their ability to enter ongoing GCs accommodates antigenic variation during the immune response.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3941467/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3941467/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shulman, Ziv -- Gitlin, Alexander D -- Targ, Sasha -- Jankovic, Mila -- Pasqual, Giulia -- Nussenzweig, Michel C -- Victora, Gabriel D -- 5DP5OD012146-02/OD/NIH HHS/ -- AI037526-19/AI/NIAID NIH HHS/ -- AI072529-06/AI/NIAID NIH HHS/ -- AI100663-01/AI/NIAID NIH HHS/ -- DP5 OD012146/OD/NIH HHS/ -- R01 AI037526/AI/NIAID NIH HHS/ -- R01 AI072529/AI/NIAID NIH HHS/ -- R37 AI037526/AI/NIAID NIH HHS/ -- T32GM07739/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2013 Aug 9;341(6146):673-7. doi: 10.1126/science.1241680. Epub 2013 Jul 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10021, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23887872" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigenic Variation ; B-Lymphocytes/cytology/*immunology ; Clone Cells ; Germinal Center/cytology/*immunology ; Mice ; T-Lymphocytes, Helper-Inducer/cytology/*immunology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 3
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    Dynamic signaling by T follicular helper cells during germinal center B cell selection (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-08-30
    Description: T follicular helper (T(FH)) cells select high-affinity, antibody-producing B cells for clonal expansion in germinal centers (GCs), but the nature of their interaction is not well defined. Using intravital imaging, we found that selection is mediated by large but transient contacts between T(FH) and GC B cells presenting the highest levels of cognate peptide bound to major histocompatibility complex II. These interactions elicited transient and sustained increases in T(FH) intracellular free calcium (Ca(2+)) that were associated with T(FH) cell coexpression of the cytokines interleukin-4 and -21. However, increased intracellular Ca(2+) did not arrest TFH cell migration. Instead, T(FH) cells remained motile and continually scanned the surface of many GC B cells, forming short-lived contacts that induced selection through further repeated transient elevations in intracellular Ca(2+).〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4519234/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4519234/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shulman, Ziv -- Gitlin, Alexander D -- Weinstein, Jason S -- Lainez, Begona -- Esplugues, Enric -- Flavell, Richard A -- Craft, Joseph E -- Nussenzweig, Michel C -- AI037526-19/AI/NIAID NIH HHS/ -- AI072529-06/AI/NIAID NIH HHS/ -- AI100663-02/AI/NIAID NIH HHS/ -- AR053495-08/AR/NIAMS NIH HHS/ -- AR40072-24/AR/NIAMS NIH HHS/ -- P30 AR053495/AR/NIAMS NIH HHS/ -- R01 AI037526/AI/NIAID NIH HHS/ -- R01 AI072529/AI/NIAID NIH HHS/ -- R01 AR040072/AR/NIAMS NIH HHS/ -- R21 AR063942/AR/NIAMS NIH HHS/ -- T32GM07739/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2014 Aug 29;345(6200):1058-62. doi: 10.1126/science.1257861.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA. ; Department of Internal Medicine (Rheumatology), School of Medicine, Yale University, New Haven, CT 06520, USA. ; Department of Immunobiology, School of Medicine, Yale University New Haven, CT 06520, USA. ; Department of Immunobiology, School of Medicine, Yale University New Haven, CT 06520, USA. Howard Hughes Medical Institute (HHMI). ; Department of Internal Medicine (Rheumatology), School of Medicine, Yale University, New Haven, CT 06520, USA. Department of Immunobiology, School of Medicine, Yale University New Haven, CT 06520, USA. ; Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA. Howard Hughes Medical Institute (HHMI). nussen@rockefeller.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25170154" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; B-Lymphocytes/*immunology ; Calcium Signaling/*immunology ; Germinal Center/*immunology ; Green Fluorescent Proteins/metabolism ; Histocompatibility Antigens Class II/*immunology ; Interleukin-4/immunology ; Interleukins/immunology ; Mice ; Mice, Knockout ; Molecular Imaging ; T-Lymphocytes, Helper-Inducer/*immunology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 4
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    HUMORAL IMMUNITY. T cell help controls the speed of the cell cycle in germinal center B cells (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-07-18
    Description: The germinal center (GC) is a microanatomical compartment wherein high-affinity antibody-producing B cells are selectively expanded. B cells proliferate and mutate their antibody genes in the dark zone (DZ) of the GC and are then selected by T cells in the light zone (LZ) on the basis of affinity. Here, we show that T cell help regulates the speed of cell cycle phase transitions and DNA replication of GC B cells. Genome sequencing and single-molecule analyses revealed that T cell help shortens S phase by regulating replication fork progression, while preserving the relative order of replication origin activation. Thus, high-affinity GC B cells are selected by a mechanism that involves prolonged dwell time in the DZ where selected cells undergo accelerated cell cycles.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gitlin, Alexander D -- Mayer, Christian T -- Oliveira, Thiago Y -- Shulman, Ziv -- Jones, Mathew J K -- Koren, Amnon -- Nussenzweig, Michel C -- 1F30AI109903-01/AI/NIAID NIH HHS/ -- 1UM1 AI100663-01/AI/NIAID NIH HHS/ -- AI037526-19/AI/NIAID NIH HHS/ -- AI072529-06/AI/NIAID NIH HHS/ -- T32GM07739/GM/NIGMS NIH HHS/ -- UM1 AI100663/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Aug 7;349(6248):643-6. doi: 10.1126/science.aac4919. Epub 2015 Jul 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA. ; Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. ; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. ; Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA. Howard Hughes Medical Institute (HHMI), The Rockefeller University, New York, NY 10065, USA. nussen@rockefeller.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26184917" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; B-Lymphocytes/*cytology ; Cell Cycle/genetics/*immunology ; Cell Proliferation ; DNA Replication/genetics/*immunology ; Gene Expression Regulation ; Germinal Center/*cytology ; Immunity, Humoral/*genetics ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; S Phase/genetics/immunology ; T-Lymphocytes/*immunology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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