B Cell-Intrinsic mTORC1 Promotes Germinal Center-Defining Transcription Factor Gene Expression, Somatic Hypermutation, and Memory B Cell Generation in Humoral Immunity.
Identifieur interne : 000650 ( Main/Exploration ); précédent : 000649; suivant : 000651B Cell-Intrinsic mTORC1 Promotes Germinal Center-Defining Transcription Factor Gene Expression, Somatic Hypermutation, and Memory B Cell Generation in Humoral Immunity.
Auteurs : Ariel L. Raybuck [États-Unis] ; Sung Hoon Cho [États-Unis] ; Jingxin Li [États-Unis] ; Meredith C. Rogers [États-Unis] ; Keunwook Lee [États-Unis] ; Christopher L. Williams [États-Unis] ; Mark Shlomchik [États-Unis] ; James W. Thomas [États-Unis] ; Jin Chen [États-Unis] ; John V. Williams [États-Unis] ; Mark R. Boothby [États-Unis]Source :
- Journal of immunology (Baltimore, Md. : 1950) [ 1550-6606 ] ; 2018.
Descripteurs français
- KwdFr :
- Activation des lymphocytes (immunologie), Animaux (MeSH), Centre germinatif (immunologie), Complexe-1 cible mécanistique de la rapamycine (immunologie), Différenciation cellulaire (immunologie), Expression des gènes (immunologie), Facteurs de transcription (génétique), Immunité humorale (immunologie), Immunoglobuline G (immunologie), Lymphocytes B (immunologie), Mutation (immunologie), Mémoire immunologique (immunologie), Plasmocytes (immunologie), Protéines proto-oncogènes c-bcl-6 (immunologie), Souris (MeSH), Souris de lignée C57BL (MeSH), Transduction du signal (immunologie).
- MESH :
- génétique : Facteurs de transcription.
- immunologie : Activation des lymphocytes, Centre germinatif, Complexe-1 cible mécanistique de la rapamycine, Différenciation cellulaire, Expression des gènes, Immunité humorale, Immunoglobuline G, Lymphocytes B, Mutation, Mémoire immunologique, Plasmocytes, Protéines proto-oncogènes c-bcl-6, Transduction du signal.
- Animaux, Souris, Souris de lignée C57BL.
English descriptors
- KwdEn :
- Animals (MeSH), B-Lymphocytes (immunology), Cell Differentiation (immunology), Gene Expression (immunology), Germinal Center (immunology), Immunity, Humoral (immunology), Immunoglobulin G (immunology), Immunologic Memory (immunology), Lymphocyte Activation (immunology), Mechanistic Target of Rapamycin Complex 1 (immunology), Mice (MeSH), Mice, Inbred C57BL (MeSH), Mutation (immunology), Plasma Cells (immunology), Proto-Oncogene Proteins c-bcl-6 (immunology), Signal Transduction (immunology), Transcription Factors (genetics).
- MESH :
- chemical , genetics : Transcription Factors.
- chemical , immunology : Immunoglobulin G, Mechanistic Target of Rapamycin Complex 1, Proto-Oncogene Proteins c-bcl-6.
- immunology : B-Lymphocytes, Cell Differentiation, Gene Expression, Germinal Center, Immunity, Humoral, Immunologic Memory, Lymphocyte Activation, Mutation, Plasma Cells, Signal Transduction.
- Animals, Mice, Mice, Inbred C57BL.
Abstract
B lymphocytes migrate among varied microenvironmental niches during diversification, selection, and conversion to memory or Ab-secreting plasma cells. Aspects of the nutrient milieu differ within these lymphoid microenvironments and can influence signaling molecules such as the mechanistic target of rapamycin (mTOR). However, much remains to be elucidated as to the B cell-intrinsic functions of nutrient-sensing signal transducers that modulate B cell differentiation or Ab affinity. We now show that the amino acid-sensing mTOR complex 1 (mTORC1) is vital for induction of Bcl6-a key transcriptional regulator of the germinal center (GC) fate-in activated B lymphocytes. Accordingly, disruption of mTORC1 after B cell development and activation led to reduced populations of Ag-specific memory B cells as well as plasma cells and GC B cells. In addition, induction of the germ line transcript that guides activation-induced deaminase in selection of the IgG1 H chain region during class switching required mTORC1. Expression of the somatic mutator activation-induced deaminase was reduced by a lack of mTORC1 in B cells, whereas point mutation frequencies in Ag-specific GC-phenotype B cells were only halved. These effects culminated in a B cell-intrinsic defect that impacted an antiviral Ab response and drastically impaired generation of high-affinity IgG1. Collectively, these data establish that mTORC1 governs critical B cell-intrinsic mechanisms essential for establishment of GC differentiation and effective Ab production.
DOI: 10.4049/jimmunol.1701321
PubMed: 29531165
PubMed Central: PMC5893413
Affiliations:
Links toward previous steps (curation, corpus...)
Le document en format XML
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Thomas</name><affiliation wicri:level="2"><nlm:affiliation>Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 27232.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Tennessee</region></placeName><wicri:cityArea>Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University Medical Center, Nashville</wicri:cityArea></affiliation></author><author><name sortKey="Chen, Jin" sort="Chen, Jin" uniqKey="Chen J" first="Jin" last="Chen">Jin Chen</name><affiliation wicri:level="2"><nlm:affiliation>Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 27232.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Tennessee</region></placeName><wicri:cityArea>Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University Medical Center, Nashville</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:affiliation>Medical and Research Services, Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37212.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Tennessee</region></placeName><wicri:cityArea>Medical and Research Services, Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:affiliation>Program in Cancer Biology, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232; and.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Tennessee</region></placeName><wicri:cityArea>Program in Cancer Biology, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:affiliation>Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Tennessee</region></placeName><wicri:cityArea>Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville</wicri:cityArea></affiliation></author><author><name sortKey="Williams, John V" sort="Williams, John V" uniqKey="Williams J" first="John V" last="Williams">John V. Williams</name><affiliation wicri:level="2"><nlm:affiliation>Division of Infectious Diseases, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 27232.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Tennessee</region></placeName><wicri:cityArea>Division of Infectious Diseases, Department of Pediatrics, Vanderbilt University Medical Center, Nashville</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:affiliation>Department of Immunology, University of Pittsburgh Medical Center, Pittsburgh, PA 15261.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Department of Immunology, University of Pittsburgh Medical Center, Pittsburgh</wicri:cityArea></affiliation></author><author><name sortKey="Boothby, Mark R" sort="Boothby, Mark R" uniqKey="Boothby M" first="Mark R" last="Boothby">Mark R. Boothby</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232; mark.boothby@vanderbilt.edu.</nlm:affiliation><country wicri:rule="url">États-Unis</country><wicri:regionArea>Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville</wicri:regionArea><wicri:noRegion>Nashville</wicri:noRegion></affiliation><affiliation wicri:level="2"><nlm:affiliation>Medical and Research Services, Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37212.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Tennessee</region></placeName><wicri:cityArea>Medical and Research Services, Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:affiliation>Program in Cancer Biology, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232; and.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Tennessee</region></placeName><wicri:cityArea>Program in Cancer Biology, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville</wicri:cityArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2018">2018</date><idno type="RBID">pubmed:29531165</idno><idno type="pmid">29531165</idno><idno type="doi">10.4049/jimmunol.1701321</idno><idno type="pmc">PMC5893413</idno><idno type="wicri:Area/Main/Corpus">000596</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Corpus" wicri:corpus="PubMed">000596</idno><idno type="wicri:Area/Main/Curation">000596</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Curation">000596</idno><idno type="wicri:Area/Main/Exploration">000596</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">B Cell-Intrinsic mTORC1 Promotes Germinal Center-Defining Transcription Factor Gene Expression, Somatic Hypermutation, and Memory B Cell Generation in Humoral Immunity.</title><author><name sortKey="Raybuck, Ariel L" sort="Raybuck, Ariel L" uniqKey="Raybuck A" first="Ariel L" last="Raybuck">Ariel L. Raybuck</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Tennessee</region></placeName><wicri:cityArea>Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville</wicri:cityArea></affiliation></author><author><name sortKey="Cho, Sung Hoon" sort="Cho, Sung Hoon" uniqKey="Cho S" first="Sung Hoon" last="Cho">Sung Hoon Cho</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Tennessee</region></placeName><wicri:cityArea>Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville</wicri:cityArea></affiliation></author><author><name sortKey="Li, Jingxin" sort="Li, Jingxin" uniqKey="Li J" first="Jingxin" last="Li">Jingxin Li</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Tennessee</region></placeName><wicri:cityArea>Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville</wicri:cityArea></affiliation></author><author><name sortKey="Rogers, Meredith C" sort="Rogers, Meredith C" uniqKey="Rogers M" first="Meredith C" last="Rogers">Meredith C. Rogers</name><affiliation wicri:level="2"><nlm:affiliation>Division of Infectious Diseases, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 27232.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Tennessee</region></placeName><wicri:cityArea>Division of Infectious Diseases, Department of Pediatrics, Vanderbilt University Medical Center, Nashville</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:affiliation>Department of Immunology, University of Pittsburgh Medical Center, Pittsburgh, PA 15261.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Department of Immunology, University of Pittsburgh Medical Center, Pittsburgh</wicri:cityArea></affiliation></author><author><name sortKey="Lee, Keunwook" sort="Lee, Keunwook" uniqKey="Lee K" first="Keunwook" last="Lee">Keunwook Lee</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Tennessee</region></placeName><wicri:cityArea>Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville</wicri:cityArea></affiliation></author><author><name sortKey="Williams, Christopher L" sort="Williams, Christopher L" uniqKey="Williams C" first="Christopher L" last="Williams">Christopher L. Williams</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Tennessee</region></placeName><wicri:cityArea>Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville</wicri:cityArea></affiliation></author><author><name sortKey="Shlomchik, Mark" sort="Shlomchik, Mark" uniqKey="Shlomchik M" first="Mark" last="Shlomchik">Mark Shlomchik</name><affiliation wicri:level="2"><nlm:affiliation>Department of Immunology, University of Pittsburgh Medical Center, Pittsburgh, PA 15261.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Department of Immunology, University of Pittsburgh Medical Center, Pittsburgh</wicri:cityArea></affiliation></author><author><name sortKey="Thomas, James W" sort="Thomas, James W" uniqKey="Thomas J" first="James W" last="Thomas">James W. Thomas</name><affiliation wicri:level="2"><nlm:affiliation>Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 27232.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Tennessee</region></placeName><wicri:cityArea>Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University Medical Center, Nashville</wicri:cityArea></affiliation></author><author><name sortKey="Chen, Jin" sort="Chen, Jin" uniqKey="Chen J" first="Jin" last="Chen">Jin Chen</name><affiliation wicri:level="2"><nlm:affiliation>Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 27232.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Tennessee</region></placeName><wicri:cityArea>Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University Medical Center, Nashville</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:affiliation>Medical and Research Services, Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37212.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Tennessee</region></placeName><wicri:cityArea>Medical and Research Services, Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:affiliation>Program in Cancer Biology, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232; and.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Tennessee</region></placeName><wicri:cityArea>Program in Cancer Biology, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:affiliation>Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Tennessee</region></placeName><wicri:cityArea>Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville</wicri:cityArea></affiliation></author><author><name sortKey="Williams, John V" sort="Williams, John V" uniqKey="Williams J" first="John V" last="Williams">John V. Williams</name><affiliation wicri:level="2"><nlm:affiliation>Division of Infectious Diseases, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 27232.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Tennessee</region></placeName><wicri:cityArea>Division of Infectious Diseases, Department of Pediatrics, Vanderbilt University Medical Center, Nashville</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:affiliation>Department of Immunology, University of Pittsburgh Medical Center, Pittsburgh, PA 15261.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Department of Immunology, University of Pittsburgh Medical Center, Pittsburgh</wicri:cityArea></affiliation></author><author><name sortKey="Boothby, Mark R" sort="Boothby, Mark R" uniqKey="Boothby M" first="Mark R" last="Boothby">Mark R. Boothby</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232; mark.boothby@vanderbilt.edu.</nlm:affiliation><country wicri:rule="url">États-Unis</country><wicri:regionArea>Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville</wicri:regionArea><wicri:noRegion>Nashville</wicri:noRegion></affiliation><affiliation wicri:level="2"><nlm:affiliation>Medical and Research Services, Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37212.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Tennessee</region></placeName><wicri:cityArea>Medical and Research Services, Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:affiliation>Program in Cancer Biology, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232; and.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Tennessee</region></placeName><wicri:cityArea>Program in Cancer Biology, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville</wicri:cityArea></affiliation></author></analytic><series><title level="j">Journal of immunology (Baltimore, Md. : 1950)</title><idno type="eISSN">1550-6606</idno><imprint><date when="2018" type="published">2018</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals (MeSH)</term><term>B-Lymphocytes (immunology)</term><term>Cell Differentiation (immunology)</term><term>Gene Expression (immunology)</term><term>Germinal Center (immunology)</term><term>Immunity, Humoral (immunology)</term><term>Immunoglobulin G (immunology)</term><term>Immunologic Memory (immunology)</term><term>Lymphocyte Activation (immunology)</term><term>Mechanistic Target of Rapamycin Complex 1 (immunology)</term><term>Mice (MeSH)</term><term>Mice, Inbred C57BL (MeSH)</term><term>Mutation (immunology)</term><term>Plasma Cells (immunology)</term><term>Proto-Oncogene Proteins c-bcl-6 (immunology)</term><term>Signal Transduction (immunology)</term><term>Transcription Factors (genetics)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Activation des lymphocytes (immunologie)</term><term>Animaux (MeSH)</term><term>Centre germinatif (immunologie)</term><term>Complexe-1 cible mécanistique de la rapamycine (immunologie)</term><term>Différenciation cellulaire (immunologie)</term><term>Expression des gènes (immunologie)</term><term>Facteurs de transcription (génétique)</term><term>Immunité humorale (immunologie)</term><term>Immunoglobuline G (immunologie)</term><term>Lymphocytes B (immunologie)</term><term>Mutation (immunologie)</term><term>Mémoire immunologique (immunologie)</term><term>Plasmocytes (immunologie)</term><term>Protéines proto-oncogènes c-bcl-6 (immunologie)</term><term>Souris (MeSH)</term><term>Souris de lignée C57BL (MeSH)</term><term>Transduction du signal (immunologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Transcription Factors</term></keywords><keywords scheme="MESH" type="chemical" qualifier="immunology" xml:lang="en"><term>Immunoglobulin G</term><term>Mechanistic Target of Rapamycin Complex 1</term><term>Proto-Oncogene Proteins c-bcl-6</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Facteurs de transcription</term></keywords><keywords scheme="MESH" qualifier="immunologie" xml:lang="fr"><term>Activation des lymphocytes</term><term>Centre germinatif</term><term>Complexe-1 cible mécanistique de la rapamycine</term><term>Différenciation cellulaire</term><term>Expression des gènes</term><term>Immunité humorale</term><term>Immunoglobuline G</term><term>Lymphocytes B</term><term>Mutation</term><term>Mémoire immunologique</term><term>Plasmocytes</term><term>Protéines proto-oncogènes c-bcl-6</term><term>Transduction du signal</term></keywords><keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>B-Lymphocytes</term><term>Cell Differentiation</term><term>Gene Expression</term><term>Germinal Center</term><term>Immunity, Humoral</term><term>Immunologic Memory</term><term>Lymphocyte Activation</term><term>Mutation</term><term>Plasma Cells</term><term>Signal Transduction</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Mice</term><term>Mice, Inbred C57BL</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Souris</term><term>Souris de lignée C57BL</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">B lymphocytes migrate among varied microenvironmental niches during diversification, selection, and conversion to memory or Ab-secreting plasma cells. Aspects of the nutrient milieu differ within these lymphoid microenvironments and can influence signaling molecules such as the mechanistic target of rapamycin (mTOR). However, much remains to be elucidated as to the B cell-intrinsic functions of nutrient-sensing signal transducers that modulate B cell differentiation or Ab affinity. We now show that the amino acid-sensing mTOR complex 1 (mTORC1) is vital for induction of Bcl6-a key transcriptional regulator of the germinal center (GC) fate-in activated B lymphocytes. Accordingly, disruption of mTORC1 after B cell development and activation led to reduced populations of Ag-specific memory B cells as well as plasma cells and GC B cells. In addition, induction of the germ line transcript that guides activation-induced deaminase in selection of the IgG1 H chain region during class switching required mTORC1. Expression of the somatic mutator activation-induced deaminase was reduced by a lack of mTORC1 in B cells, whereas point mutation frequencies in Ag-specific GC-phenotype B cells were only halved. These effects culminated in a B cell-intrinsic defect that impacted an antiviral Ab response and drastically impaired generation of high-affinity IgG1. Collectively, these data establish that mTORC1 governs critical B cell-intrinsic mechanisms essential for establishment of GC differentiation and effective Ab production.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">29531165</PMID><DateCompleted><Year>2019</Year><Month>04</Month><Day>10</Day></DateCompleted><DateRevised><Year>2019</Year><Month>04</Month><Day>15</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1550-6606</ISSN><JournalIssue CitedMedium="Internet"><Volume>200</Volume><Issue>8</Issue><PubDate><Year>2018</Year><Month>04</Month><Day>15</Day></PubDate></JournalIssue><Title>Journal of immunology (Baltimore, Md. : 1950)</Title><ISOAbbreviation>J Immunol</ISOAbbreviation></Journal><ArticleTitle>B Cell-Intrinsic mTORC1 Promotes Germinal Center-Defining Transcription Factor Gene Expression, Somatic Hypermutation, and Memory B Cell Generation in Humoral Immunity.</ArticleTitle><Pagination><MedlinePgn>2627-2639</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.4049/jimmunol.1701321</ELocationID><Abstract><AbstractText>B lymphocytes migrate among varied microenvironmental niches during diversification, selection, and conversion to memory or Ab-secreting plasma cells. Aspects of the nutrient milieu differ within these lymphoid microenvironments and can influence signaling molecules such as the mechanistic target of rapamycin (mTOR). However, much remains to be elucidated as to the B cell-intrinsic functions of nutrient-sensing signal transducers that modulate B cell differentiation or Ab affinity. We now show that the amino acid-sensing mTOR complex 1 (mTORC1) is vital for induction of Bcl6-a key transcriptional regulator of the germinal center (GC) fate-in activated B lymphocytes. Accordingly, disruption of mTORC1 after B cell development and activation led to reduced populations of Ag-specific memory B cells as well as plasma cells and GC B cells. In addition, induction of the germ line transcript that guides activation-induced deaminase in selection of the IgG1 H chain region during class switching required mTORC1. Expression of the somatic mutator activation-induced deaminase was reduced by a lack of mTORC1 in B cells, whereas point mutation frequencies in Ag-specific GC-phenotype B cells were only halved. These effects culminated in a B cell-intrinsic defect that impacted an antiviral Ab response and drastically impaired generation of high-affinity IgG1. Collectively, these data establish that mTORC1 governs critical B cell-intrinsic mechanisms essential for establishment of GC differentiation and effective Ab production.</AbstractText><CopyrightInformation>Copyright © 2018 by The American Association of Immunologists, Inc.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Raybuck</LastName><ForeName>Ariel L</ForeName><Initials>AL</Initials><AffiliationInfo><Affiliation>Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Cho</LastName><ForeName>Sung Hoon</ForeName><Initials>SH</Initials><Identifier Source="ORCID">0000-0002-6463-4032</Identifier><AffiliationInfo><Affiliation>Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Li</LastName><ForeName>Jingxin</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rogers</LastName><ForeName>Meredith C</ForeName><Initials>MC</Initials><Identifier Source="ORCID">0000-0003-1798-6294</Identifier><AffiliationInfo><Affiliation>Division of Infectious Diseases, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 27232.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Immunology, University of Pittsburgh Medical Center, Pittsburgh, PA 15261.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lee</LastName><ForeName>Keunwook</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Williams</LastName><ForeName>Christopher L</ForeName><Initials>CL</Initials><AffiliationInfo><Affiliation>Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Shlomchik</LastName><ForeName>Mark</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Department of Immunology, University of Pittsburgh Medical Center, Pittsburgh, PA 15261.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Thomas</LastName><ForeName>James W</ForeName><Initials>JW</Initials><Identifier Source="ORCID">0000-0002-2098-6458</Identifier><AffiliationInfo><Affiliation>Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 27232.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Chen</LastName><ForeName>Jin</ForeName><Initials>J</Initials><Identifier Source="ORCID">0000-0002-5557-2079</Identifier><AffiliationInfo><Affiliation>Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 27232.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Medical and Research Services, Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37212.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Program in Cancer Biology, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232; and.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Williams</LastName><ForeName>John V</ForeName><Initials>JV</Initials><Identifier Source="ORCID">0000-0001-8377-5175</Identifier><AffiliationInfo><Affiliation>Division of Infectious Diseases, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 27232.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Immunology, University of Pittsburgh Medical Center, Pittsburgh, PA 15261.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Boothby</LastName><ForeName>Mark R</ForeName><Initials>MR</Initials><AffiliationInfo><Affiliation>Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232; mark.boothby@vanderbilt.edu.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Medical and Research Services, Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37212.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Program in Cancer Biology, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232; and.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>S10 OD018015</GrantID><Acronym>OD</Acronym><Agency>NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R01 AI085062</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R01 AI113292</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R01 AI051448</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>T32 HL069765</GrantID><Acronym>HL</Acronym><Agency>NHLBI NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>P30 CA068485</GrantID><Acronym>CA</Acronym><Agency>NCI NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R56 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Rogers</name><name sortKey="Rogers, Meredith C" sort="Rogers, Meredith C" uniqKey="Rogers M" first="Meredith C" last="Rogers">Meredith C. Rogers</name><name sortKey="Shlomchik, Mark" sort="Shlomchik, Mark" uniqKey="Shlomchik M" first="Mark" last="Shlomchik">Mark Shlomchik</name><name sortKey="Thomas, James W" sort="Thomas, James W" uniqKey="Thomas J" first="James W" last="Thomas">James W. Thomas</name><name sortKey="Williams, Christopher L" sort="Williams, Christopher L" uniqKey="Williams C" first="Christopher L" last="Williams">Christopher L. Williams</name><name sortKey="Williams, John V" sort="Williams, John V" uniqKey="Williams J" first="John V" last="Williams">John V. Williams</name><name sortKey="Williams, John V" sort="Williams, John V" uniqKey="Williams J" first="John V" last="Williams">John V. Williams</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Bois/explor/RapamycinFungusV1/Data/Main/Exploration
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000650 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd -nk 000650 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Bois
|area= RapamycinFungusV1
|flux= Main
|étape= Exploration
|type= RBID
|clé= pubmed:29531165
|texte= B Cell-Intrinsic mTORC1 Promotes Germinal Center-Defining Transcription Factor Gene Expression, Somatic Hypermutation, and Memory B Cell Generation in Humoral Immunity.
}}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Main/Exploration/RBID.i -Sk "pubmed:29531165" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd \
| NlmPubMed2Wicri -a RapamycinFungusV1
| This area was generated with Dilib version V0.6.38. |  |