Mature IgM-expressing plasma cells sense antigen and develop competence for cytokine production upon antigenic challenge
Identifieur interne : 000786 ( Pmc/Checkpoint ); précédent : 000785; suivant : 000787Mature IgM-expressing plasma cells sense antigen and develop competence for cytokine production upon antigenic challenge
Auteurs : Pascal Blanc [France] ; Ludovic Moro-Sibilot [France] ; Lucas Barthly [France] ; Ferdinand Jagot [France] ; Sébastien This [France] ; Simon De Bernard [France] ; Laurent Buffat [France] ; Sébastien Dussurgey [France] ; Renaud Colisson [France] ; Elias Hobeika [Allemagne] ; Thierry Fest [France] ; Morgan Taillardet [France] ; Olivier Thaunat [France] ; Antoine Sicard [France] ; Paul Mondière [France] ; Laurent Genestier [France] ; Stephen L. Nutt [Australie] ; Thierry Defrance [France]Source :
- Nature Communications [ 2041-1723 ] ; 2016.
Abstract
Dogma holds that plasma cells, as opposed to B cells, cannot bind antigen because they have switched from expression of membrane-bound immunoglobulins (Ig) that constitute the B-cell receptor (BCR) to production of the secreted form of immunoglobulins. Here we compare the phenotypical and functional attributes of plasma cells generated by the T-cell-dependent and T-cell-independent forms of the hapten NP. We show that the nature of the secreted Ig isotype, rather than the chemical structure of the immunizing antigen, defines two functionally distinct populations of plasma cells. Fully mature IgM-expressing plasma cells resident in the bone marrow retain expression of a functional BCR, whereas their IgG+ counterparts do not. Antigen boost modifies the gene expression profile of IgM+ plasma cells and initiates a cytokine production program, characterized by upregulation of CCL5 and IL-10. Our results demonstrate that IgM-expressing plasma cells can sense antigen and acquire competence for cytokine production upon antigenic challenge.
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DOI: 10.1038/ncomms13600
PubMed: 27924814
PubMed Central: 5150646
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Lyon</institution>, 21 Avenue Tony Garnier, 69007 Lyon,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Moro Sibilot, Ludovic" sort="Moro Sibilot, Ludovic" uniqKey="Moro Sibilot L" first="Ludovic" last="Moro-Sibilot">Ludovic Moro-Sibilot</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>CIRI, INSERM, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, École Normale Supérieure de Lyon, Univ. Lyon</institution>, 21 Avenue Tony Garnier, 69007 Lyon,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Barthly, Lucas" sort="Barthly, Lucas" uniqKey="Barthly L" first="Lucas" last="Barthly">Lucas Barthly</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>CIRI, INSERM, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, École Normale Supérieure de Lyon, Univ. Lyon</institution>, 21 Avenue Tony Garnier, 69007 Lyon,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Jagot, Ferdinand" sort="Jagot, Ferdinand" uniqKey="Jagot F" first="Ferdinand" last="Jagot">Ferdinand Jagot</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>CIRI, INSERM, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, École Normale Supérieure de Lyon, Univ. Lyon</institution>, 21 Avenue Tony Garnier, 69007 Lyon,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="This, Sebastien" sort="This, Sebastien" uniqKey="This S" first="Sébastien" last="This">Sébastien This</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>CIRI, INSERM, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, École Normale Supérieure de Lyon, Univ. Lyon</institution>, 21 Avenue Tony Garnier, 69007 Lyon,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="De Bernard, Simon" sort="De Bernard, Simon" uniqKey="De Bernard S" first="Simon" last="De Bernard">Simon De Bernard</name><affiliation wicri:level="1"><nlm:aff id="a2"><institution>AltraBio SAS</institution>, 30 rue Pre Gaudry, 69007 Lyon,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Buffat, Laurent" sort="Buffat, Laurent" uniqKey="Buffat L" first="Laurent" last="Buffat">Laurent Buffat</name><affiliation wicri:level="1"><nlm:aff id="a2"><institution>AltraBio SAS</institution>, 30 rue Pre Gaudry, 69007 Lyon,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Dussurgey, Sebastien" sort="Dussurgey, Sebastien" uniqKey="Dussurgey S" first="Sébastien" last="Dussurgey">Sébastien Dussurgey</name><affiliation wicri:level="1"><nlm:aff id="a3"><institution>INSERM SFR Biosciences Gerland, UMS3444/US8</institution>, 50 Avenue Tony Garnier, 69007 Lyon,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Colisson, Renaud" sort="Colisson, Renaud" uniqKey="Colisson R" first="Renaud" last="Colisson">Renaud Colisson</name><affiliation wicri:level="1"><nlm:aff id="a4"><institution>eBioscience, An Affymetrix Company</institution>, 140 bis Rue de Rennes, 75006 Paris,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Hobeika, Elias" sort="Hobeika, Elias" uniqKey="Hobeika E" first="Elias" last="Hobeika">Elias Hobeika</name><affiliation wicri:level="1"><nlm:aff id="a5"><institution>Institute of Immunology, University Hospital</institution>, Albert Einstein Allee 11, Ulm 89073,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Fest, Thierry" sort="Fest, Thierry" uniqKey="Fest T" first="Thierry" last="Fest">Thierry Fest</name><affiliation wicri:level="1"><nlm:aff id="a6"><institution>INSERM, UMR917</institution>, F-35043 Rennes,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a7"><institution>Pôle de Biologie, Centre Hospitalier Universitaire</institution>, 35033 Rennes,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a8"><institution>Université de Rennes 1</institution>, F-35065 Rennes,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Taillardet, Morgan" sort="Taillardet, Morgan" uniqKey="Taillardet M" first="Morgan" last="Taillardet">Morgan Taillardet</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>CIRI, INSERM, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, École Normale Supérieure de Lyon, Univ. Lyon</institution>, 21 Avenue Tony Garnier, 69007 Lyon,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Thaunat, Olivier" sort="Thaunat, Olivier" uniqKey="Thaunat O" first="Olivier" last="Thaunat">Olivier Thaunat</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>CIRI, INSERM, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, École Normale Supérieure de Lyon, Univ. Lyon</institution>, 21 Avenue Tony Garnier, 69007 Lyon,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Sicard, Antoine" sort="Sicard, Antoine" uniqKey="Sicard A" first="Antoine" last="Sicard">Antoine Sicard</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>CIRI, INSERM, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, École Normale Supérieure de Lyon, Univ. Lyon</institution>, 21 Avenue Tony Garnier, 69007 Lyon,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Mondiere, Paul" sort="Mondiere, Paul" uniqKey="Mondiere P" first="Paul" last="Mondière">Paul Mondière</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>CIRI, INSERM, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, École Normale Supérieure de Lyon, Univ. Lyon</institution>, 21 Avenue Tony Garnier, 69007 Lyon,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Genestier, Laurent" sort="Genestier, Laurent" uniqKey="Genestier L" first="Laurent" last="Genestier">Laurent Genestier</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>CIRI, INSERM, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, École Normale Supérieure de Lyon, Univ. Lyon</institution>, 21 Avenue Tony Garnier, 69007 Lyon,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Nutt, Stephen L" sort="Nutt, Stephen L" uniqKey="Nutt S" first="Stephen L." last="Nutt">Stephen L. Nutt</name><affiliation wicri:level="1"><nlm:aff id="a9"><institution>The Walter and Eliza Hall Institute of Medical Research</institution>, 1G Royal Parade, Parkville, Victoria 3052,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a10"><institution>Department of Medical Biology, University of Melbourne</institution>, Parkville, Victoria 3010,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Defrance, Thierry" sort="Defrance, Thierry" uniqKey="Defrance T" first="Thierry" last="Defrance">Thierry Defrance</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>CIRI, INSERM, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, École Normale Supérieure de Lyon, Univ. Lyon</institution>, 21 Avenue Tony Garnier, 69007 Lyon,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Nature Communications</title><idno type="eISSN">2041-1723</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Dogma holds that plasma cells, as opposed to B cells, cannot bind antigen because they have switched from expression of membrane-bound immunoglobulins (Ig) that constitute the B-cell receptor (BCR) to production of the secreted form of immunoglobulins. Here we compare the phenotypical and functional attributes of plasma cells generated by the T-cell-dependent and T-cell-independent forms of the hapten NP. We show that the nature of the secreted Ig isotype, rather than the chemical structure of the immunizing antigen, defines two functionally distinct populations of plasma cells. Fully mature IgM-expressing plasma cells resident in the bone marrow retain expression of a functional BCR, whereas their IgG<sup>+</sup> counterparts do not. Antigen boost modifies the gene expression profile of IgM<sup>+</sup> plasma cells and initiates a cytokine production program, characterized by upregulation of CCL5 and IL-10. Our results demonstrate that IgM-expressing plasma cells can sense antigen and acquire competence for cytokine production upon antigenic challenge.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Horcher, M" uniqKey="Horcher M">M. Horcher</name></author><author><name sortKey="Souabni, A" uniqKey="Souabni A">A. Souabni</name></author><author><name sortKey="Busslinger, M" uniqKey="Busslinger M">M. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Nat Commun</journal-id><journal-id journal-id-type="iso-abbrev">Nat Commun</journal-id><journal-title-group><journal-title>Nature Communications</journal-title></journal-title-group><issn pub-type="epub">2041-1723</issn><publisher><publisher-name>Nature Publishing Group</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">27924814</article-id><article-id pub-id-type="pmc">5150646</article-id><article-id pub-id-type="pii">ncomms13600</article-id><article-id pub-id-type="doi">10.1038/ncomms13600</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Mature IgM-expressing plasma cells sense antigen and develop competence for cytokine production upon antigenic challenge</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Blanc</surname><given-names>Pascal</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Moro-Sibilot</surname><given-names>Ludovic</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Barthly</surname><given-names>Lucas</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Jagot</surname><given-names>Ferdinand</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>This</surname><given-names>Sébastien</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>de Bernard</surname><given-names>Simon</given-names></name><xref ref-type="aff" rid="a2">2</xref></contrib><contrib contrib-type="author"><name><surname>Buffat</surname><given-names>Laurent</given-names></name><xref ref-type="aff" rid="a2">2</xref></contrib><contrib contrib-type="author"><name><surname>Dussurgey</surname><given-names>Sébastien</given-names></name><xref ref-type="aff" rid="a3">3</xref></contrib><contrib contrib-type="author"><name><surname>Colisson</surname><given-names>Renaud</given-names></name><xref ref-type="aff" rid="a4">4</xref></contrib><contrib contrib-type="author"><name><surname>Hobeika</surname><given-names>Elias</given-names></name><xref ref-type="aff" rid="a5">5</xref></contrib><contrib contrib-type="author"><name><surname>Fest</surname><given-names>Thierry</given-names></name><xref ref-type="aff" rid="a6">6</xref><xref ref-type="aff" rid="a7">7</xref><xref ref-type="aff" rid="a8">8</xref></contrib><contrib contrib-type="author"><name><surname>Taillardet</surname><given-names>Morgan</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Thaunat</surname><given-names>Olivier</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Sicard</surname><given-names>Antoine</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Mondière</surname><given-names>Paul</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Genestier</surname><given-names>Laurent</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Nutt</surname><given-names>Stephen L.</given-names></name><xref ref-type="aff" rid="a9">9</xref><xref ref-type="aff" rid="a10">10</xref></contrib><contrib contrib-type="author"><name><surname>Defrance</surname><given-names>Thierry</given-names></name><xref ref-type="corresp" rid="c1">a</xref><xref ref-type="aff" rid="a1">1</xref></contrib><aff id="a1"><label>1</label><institution>CIRI, INSERM, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, École Normale Supérieure de Lyon, Univ. Lyon</institution>, 21 Avenue Tony Garnier, 69007 Lyon,<country>France</country></aff><aff id="a2"><label>2</label><institution>AltraBio SAS</institution>, 30 rue Pre Gaudry, 69007 Lyon,<country>France</country></aff><aff id="a3"><label>3</label><institution>INSERM SFR Biosciences Gerland, UMS3444/US8</institution>, 50 Avenue Tony Garnier, 69007 Lyon,<country>France</country></aff><aff id="a4"><label>4</label><institution>eBioscience, An Affymetrix Company</institution>, 140 bis Rue de Rennes, 75006 Paris,<country>France</country></aff><aff id="a5"><label>5</label><institution>Institute of Immunology, University Hospital</institution>, Albert Einstein Allee 11, Ulm 89073,<country>Germany</country></aff><aff id="a6"><label>6</label><institution>INSERM, UMR917</institution>, F-35043 Rennes,<country>France</country></aff><aff id="a7"><label>7</label><institution>Pôle de Biologie, Centre Hospitalier Universitaire</institution>, 35033 Rennes,<country>France</country></aff><aff id="a8"><label>8</label><institution>Université de Rennes 1</institution>, F-35065 Rennes,<country>France</country></aff><aff id="a9"><label>9</label><institution>The Walter and Eliza Hall Institute of Medical Research</institution>, 1G Royal Parade, Parkville, Victoria 3052,<country>Australia</country></aff><aff id="a10"><label>10</label><institution>Department of Medical Biology, University of Melbourne</institution>, Parkville, Victoria 3010,<country>Australia</country></aff></contrib-group><author-notes><corresp id="c1"><label>a</label><email>thierry.defrance@inserm.fr</email></corresp></author-notes><pub-date pub-type="epub"><day>07</day><month>12</month><year>2016</year></pub-date><pub-date pub-type="collection"><year>2016</year></pub-date><volume>7</volume><elocation-id>13600</elocation-id><history><date date-type="received"><day>28</day><month>01</month><year>2016</year></date><date date-type="accepted"><day>17</day><month>10</month><year>2016</year></date></history><permissions><copyright-statement>Copyright © 2016, The Author(s)</copyright-statement><copyright-year>2016</copyright-year><copyright-holder>The Author(s)</copyright-holder><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/4.0/"><pmc-comment>author-paid</pmc-comment>
<license-p>This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link></license-p></license></permissions><abstract><p>Dogma holds that plasma cells, as opposed to B cells, cannot bind antigen because they have switched from expression of membrane-bound immunoglobulins (Ig) that constitute the B-cell receptor (BCR) to production of the secreted form of immunoglobulins. Here we compare the phenotypical and functional attributes of plasma cells generated by the T-cell-dependent and T-cell-independent forms of the hapten NP. We show that the nature of the secreted Ig isotype, rather than the chemical structure of the immunizing antigen, defines two functionally distinct populations of plasma cells. Fully mature IgM-expressing plasma cells resident in the bone marrow retain expression of a functional BCR, whereas their IgG<sup>+</sup> counterparts do not. Antigen boost modifies the gene expression profile of IgM<sup>+</sup> plasma cells and initiates a cytokine production program, characterized by upregulation of CCL5 and IL-10. Our results demonstrate that IgM-expressing plasma cells can sense antigen and acquire competence for cytokine production upon antigenic challenge.</p></abstract><abstract abstract-type="web-summary"><p>Plasma cells produce secreted antibodies and are thought to lack expression of the membrane-bound immunoglobulins that constitute B-cell receptors. Here the authors show that IgM-expressing plasma cells maintain B-cell receptor expression and initiate cytokine production following antigen stimulation.</p></abstract></article-meta></front><floats-group><fig id="f1"><label>Figure 1</label><caption><title>BM plasma cells induced by NP-dextran retain expression of membrane Igs.</title><p>(<bold>a</bold>) NP-binding capacity of spleen and BM plasma cells after immunization with NP-KLH or NP-dextran. Numbers on the contour plots indicate the proportions of NP-specific plasma cells expressed as percentages of total BM plasma cells. (<bold>b</bold>) Compiled data illustrating the NP-binding capacity of TD and TI BM plasma cells at different time points after immunization. (<bold>c</bold>) Compiled data illustrating quantitation of the absolute numbers of BM NP-specific plasma cells at different time points after immunization. In <bold>b</bold> and <bold>c</bold>, data are expressed as means±s.d. of the values obtained in three independent experiments with three mice per time point. (<bold>d</bold>) Frequencies of polyclonal (all ASCs) and NP-specific ASCs assessed by ELISPOT in sorted NP<sup>+</sup> and NP<sup>−</sup> TD and TI BM plasma cells. Data are means±s.d. values of triplicate determinations gathered from three independent experiments in which NP<sup>+</sup> and NP<sup>−</sup> plasma cells were sorted from the pooled BM of five mice. (<bold>e</bold>) q-RT-PCR analysis of the membrane and secreted transcripts for the μ, γ2b, γ2c and γ3 Ig isotypes in B cells and sorted NP-specific TI and TD BM plasma cells. Results are expressed as relative quantity of mRNA after normalization to GAPDH expression. Data are means±s.d. of the values obtained in two independent experiments in which NP-specific plasma cells were sorted from pools of five immunized mice. (<bold>f</bold>) Frequency of BM ASCs producing IgM, IgG2b, IgG2c and IgG3 Abs after immunization with NP-KLH or NP-dextran. Data are means±s.d. of the values gathered from two independent experiments with three mice per group. (<bold>g</bold>) Density of expression of Ig lambda light chains by NP-specific TI and TD BM plasma cells. The bar chart on the right shows a compilation of the MFI values for Ig lambda stainings gathered from three independent experiments with three mice per group. The staining control was performed with an isotype-matched unrelated mAb. All experiments were conducted on <italic>Blimp</italic><sup><italic>gfp/+</italic></sup> mice. For experiments shown in <bold>d</bold>–<bold>g</bold>, plasma cells were recovered 45 days after immunization. NS: non significant, *<italic>P</italic><0.05, **<italic>P</italic><0.01 and ***<italic>P</italic><0.001 (Mann–Whitney test). PC, plasma cells.</p></caption><graphic xlink:href="ncomms13600-f1"></graphic></fig><fig id="f2"><label>Figure 2</label><caption><title>NP-specific BM ASCs induced by NP-dextran display a plasma cell identity.</title><p>(<bold>a</bold>) Flow plots of Blimp-1/GFP (<bold>a</bold>), Pax5 (<bold>c</bold>) and CD19 (<bold>d</bold>) expression by splenic B cells, TD and TI splenic PB (6 days post-immunization), TD and TI BM plasma cells (30 days post-immunization). A compilation of the Blimp-1, Pax5 and CD19 MFI values is shown on the right of <bold>a</bold>,<bold>c</bold> and <bold>d</bold>. Cells lacking the B lineage and plasma cells markers (B220<sup>−</sup>/CD19<sup>−</sup>/GFP<sup>−</sup>, see gates in <xref ref-type="supplementary-material" rid="S1">Supplementary Fig. 1b</xref>) were used as negative staining controls (gray-filled histograms). (<bold>b</bold>) Quantification of the Blimp-1 expression levels by NP-specific splenic PB (sp 6) and BM plasma cells at different time points after immunization. The bar charts in <bold>a</bold>,<bold>c</bold> and <bold>d</bold> and the graph shown in <bold>b</bold> illustrate the means±s.d. values gathered from two separate experiments each conducted with four individual mice. <italic>P</italic> values were calculated with the Mann–Whitney test. (<bold>e</bold>) Flowplots of CD22, IgD, MHCII I-A<sup>b</sup> and CD20 expression by mature BM B cells, polyclonal BM plasma cells (all plasma cells) and NP-specific TI plasma cells, 30 days after NP-dextran immunization. Non-B/non-plasma cells cells (gray-filled histograms) were used as negative staining controls. All experiments were conducted with <italic>Blimp</italic><sup><italic>gfp/</italic>+</sup> mice. PC, plasma cells.</p></caption><graphic xlink:href="ncomms13600-f2"></graphic></fig><fig id="f3"><label>Figure 3</label><caption><title>NP-specific BM plasma cells induced by NP-dextran are quiescent.</title><p>BrdU (<bold>a</bold>) and Ki67 stainings (<bold>b</bold>) were conducted on NP-specific BM TI plasma cells and Mo/Mp progenitors (left and right contour plots, respectively) at day 8 and 32 after immunization of <italic>Blimp</italic><sup><italic>gfp/+</italic></sup> mice with NP-dextran. The staining control was performed with an isotype- and fluorochrome-matched unrelated mAb. Numbers shown on the contour plots indicate: (i) the % of NP-binding BrdU<sup>+</sup> or Ki67<sup>+</sup> plasma cells among the whole BM plasma cells population, (ii) the % of BrdU<sup>+</sup> or Ki67<sup>+</sup> Mo/Mp progenitors, (<bold>c</bold>) and (<bold>e</bold>) Compilations of the Ki67 and BrdU staining data. Results are expressed as % BrdU<sup>+</sup> or Ki67<sup>+</sup> cells among the NP-specific plasma cells and Mo/Mp progenitor populations. (<bold>d</bold>) Analysis of the staining intensity (MFI) of BrdU<sup>+</sup> cells in the NP-specific plasma cells or Mo/Mp gates at different time points after immunization. Data shown in <bold>c</bold>,<bold>d</bold> and <bold>e</bold> represent the means±s.d. of the values gathered from two separate experiments conducted with four individual mice each. <italic>P</italic> values were calculated with the Mann–Whitney test.</p></caption><graphic xlink:href="ncomms13600-f3"></graphic></fig><fig id="f4"><label>Figure 4</label><caption><title>NP-specific T-cell-independent BM plasma cells express a functional BCR.</title><p>(<bold>a</bold>) Expression of Igα and Igβ by splenic B cells and NP-specific BM plasma cells 45 days after NP-KLH or NP-dextran immunization. (<bold>b</bold>) Compilation of the MFI values of the Igα and Igβ stainings shown in <bold>a</bold>. (<bold>c</bold>) Pattern of Igα expression by plasma cells using Igα-reporter mice, 70 days after NP-dextran or NP-KLH immunization. From left to right: expression of GFP/Igα by enriched BM plasma cells cells, polyclonal plasma cells, NP-specific TD and TI plasma cells, respectively. (<bold>d</bold>) BCR-induced phosphorylation of Syk (upper panels) and Blnk (lower panels) in NP-binding (NP<sup>+</sup>) and non NP-binding (NP<sup>−</sup>) B cells, NP-specific TI and TD BM plasma cells after <italic>in vitro</italic> stimulation with NP-dextran. (<bold>e</bold>) Compilation of the delta MFI values for Syk (top) and Blnk (bottom) after <italic>in vitro</italic> stimulation with NP-dextran or NP-KLH. (<bold>f</bold>) Ca<sup>++</sup> mobilization induced by BCR ligation in B cells (left) or TI BM plasma cells (right) after <italic>in vitro</italic> culture with the indicated stimuli. Graphs illustrate Indo 1 fluorescence traces versus time. The <italic>y</italic> axis shows the indo-1 violet to blue fluorescence ratio, an indicator of intracellular Ca<sup>++</sup> levels. (<bold>g</bold>) BM plasma cells were enriched from <italic>Blimp</italic><sup><italic>gfp/+</italic></sup> mice 45 days after immunization with NP-dextran, incubated with flash red-conjugated polystyrene beads coated with NP-OVA and stained with LAMP-1 and p-Erk-specific mAbs after permeabilization. Cells were analysed by epifluorescence microscopy in flow (scale bar: 10 μM). The figure depicts representative images of plasma cells that have (left panel) or have not (right panel) internalized antigen. BF: brightfield. Data in <bold>b</bold>–<bold>e</bold> represent the means±s.d. of the values gathered from three separate experiments conducted with three mice each. <italic>P</italic> values were calculated with the Mann–Whitney test. Data in <bold>f</bold>–<bold>g</bold> are representative of two experiments conducted with plasma cells enriched from pools of four mice. Staining controls (gray-filled histograms): isotype-matched unrelated mAb (<bold>a</bold>), non-B/non plasma cells (<bold>c</bold>), unstimulated cells (<bold>d</bold>). Mice: C57Bl/6 (<bold>a</bold>), <italic>mb-1/mEGFP</italic> heterozygous mice (<bold>c</bold>), QM X C57Bl/6 F1 mice (B cells in <bold>d</bold>,<bold>f</bold>), <italic>Blimp</italic><sup><italic>gfp/+</italic></sup> mice (TD and TI plasma cells in <bold>d</bold>,<bold>g</bold>), QM X <italic>Blimp</italic><sup><italic>gfp/+</italic></sup> mice (plasma cells in <bold>f</bold>). PC, plasma cells.</p></caption><graphic xlink:href="ncomms13600-f4"></graphic></fig><fig id="f5"><label>Figure 5</label><caption><title>Maintenance of the BCR on plasma cells is associated with IgM expression.</title><p>(<bold>a</bold>) sIgM expression by TD and TI NP-specific splenic PB (day 5) and BM plasma cells. Low and high NP-binding cells are gated in black and red, respectively. (<bold>b</bold>) Intracytoplasmic staining of BM TD plasma cells with NP-PE (top) and subdivision of NP-specific plasma cells according to cytoplasmic expression of IgG1 and IgM (bottom). (<bold>c</bold>) Patterns of Blnk phosphorylation in IgM<sup>+</sup> and IgM<sup>−</sup> NP-specific TD plasma cells in response to NP-dextran, anti-IgM or anti-Igs F(ab′)2 Abs (red histograms). On the right, compilation of the delta MFI values for the stainings displayed on the left. (<bold>d</bold>) NP-binding capacity of TD or TI BM plasma cells recovered from AID<sup>+/+</sup> or AID<sup>−/−</sup> mice. On the right, compilation of the NP-binding MFI values for the stainings displayed on the left. (<bold>e</bold>) Syk and Blnk phosphorylation profiles of NP-specific TD BM plasma cells recovered from AID<sup>−/−</sup> mice, upon <italic>in vitro</italic> stimulation with NP-dextran (top) or NP-KLH (bottom). On the right, compilation of the delta MFI values for the stainings displayed on the left. (<bold>f</bold>) Enriched polyclonal BM plasma cells from naïve mice were stained for intracytoplasmic IgM, IgA and IgG1. (<bold>g</bold>) (top) Expression of kappa/lambda Ig light chains in the four plasma cells populations gated in <bold>f</bold>. The bar chart (bottom) shows a compilation of the MFI values for the kappa/lambda stainings displayed in the top panel. (<bold>h</bold>) Enriched polyclonal BM plasma cells from naïve mice were stimulated <italic>ex vivo</italic> with anti-IgM or anti-Igs F(ab')2 Abs and stained with anti-IgM, IgA, IgG1 and p-Blnk mAbs (red histograms). Plasma cells were recovered 45 days after immunization in all experiments. Data in <bold>c</bold>, <bold>d</bold> and <bold>e</bold> represent the means±s.d. of the values gathered from three separate experiments conducted with three mice each. Data in <bold>g</bold> and <bold>h</bold> represent the means±s.d. of the values gathered from two separate experiments conducted with four mice each. <italic>P</italic> values were calculated with the Mann-Whitney test. Mice: C57Bl/6 (<bold>f</bold>–<bold>h</bold>), <italic>Blimp</italic><sup><italic>gfp/+</italic></sup> (<bold>a</bold>,<bold>b</bold>), AID <sup>−/−</sup> (<bold>e</bold>). Staining controls (gray-filled histograms): unstimulated cells (<bold>c</bold>,<bold>e</bold>,<bold>h</bold>), isotype-matched unrelated control mAb (<bold>g</bold>). PC, plasma cells.</p></caption><graphic xlink:href="ncomms13600-f5"></graphic></fig><fig id="f6"><label>Figure 6</label><caption><title><bold>Antigen challenge modifies the gene expression profile of IgM</bold><sup><bold>+</bold></sup><bold>BM plasma cells.</bold></title><p>(<bold>a</bold>) <italic>Blimp</italic><sup><italic>gfp/+</italic></sup> mice were primed sc with NP-dextran or NP-KLH and boosted iv at day 60 with NP-dextran (boost) or injected with PBS (control). NP-specific BM plasma cells were analysed 12 h after secondary immunization for CD69 expression (red histograms). Staining profiles obtained with the isotype-matched unrelated control mAb are depicted as gray-filled histograms. (<bold>b</bold>) Principal component analysis (PCA) of the gene expression profiles of unstimulated (control) and antigen-stimulated (boost) NP-specific TI BM plasma cells. The two groups of experimental samples (<italic>n</italic>=5 for each group) are projected on the first two principal components that account for 33.4% of the variance. (<bold>c</bold>) Dendrogram of the 1,000 most differentially-expressed genes between unstimulated (control) and antigen-stimulated (boost) NP-specific IgM<sup>+</sup> BM plasma cells. The analysis has been conducted on five distinct samples for each experimental group. (<bold>d</bold>) Heatmap of the 13 most significantly differentially-expressed genes associated with the GO terms: cytokine production and regulation of cytokine production. (<bold>e</bold>) Impact of antigen stimulation on GFP/IL-10 expression by NP-specific TI plasma cells from IL-10 reporter Vert-X mice. Vert-X mice were injected iv with PBS 45 days after priming with NP-dextran. IgM-expressing plasma cells (left) and NP-binding plasma cells (right) BM plasma cells were analysed for their expression of GFP. Plasma cells were gated as CD138<sup>hi</sup>/Ly6c<sup>+</sup> cells as shown in <xref ref-type="supplementary-material" rid="S1">Supplementary Fig. 1c</xref>. Representative of two experiments conducted with four mice each. The bar charts show a compilation of the GFP MFI values for NP-specific plasma cells 12 h after NP-dextran boost <italic>in vivo</italic> or injection of PBS boosted (boost) or not (ctrl) with NP-dextran <italic>in vivo</italic>. Data represent the means±s.d. of the values gathered from two separate experiments with four mice per group.</p></caption><graphic xlink:href="ncomms13600-f6"></graphic></fig><table-wrap position="float" id="t1"><label>Table 1</label><caption><title>Differentially expressed genes in the antigen-stimulated IgM<sup>+</sup> plasma cell group as compared with the unstimulated IgM<sup>+</sup> plasma cell group.</title></caption><table frame="hsides" rules="groups" border="1"><colgroup><col align="left"></col><col align="left"></col><col align="center"></col><col align="center"></col></colgroup><thead valign="bottom"><tr><th align="left" valign="top" charoff="50"><bold>Gene symbol</bold></th><th align="left" valign="top" charoff="50"><bold>Gene name</bold></th><th align="center" valign="top" charoff="50"><bold>FC</bold></th><th align="center" valign="top" charoff="50"><italic><bold>q</bold></italic><bold>value</bold></th></tr></thead><tbody valign="top"><tr><td colspan="4" align="center" valign="top" charoff="50"><italic>Differentially expressed genes, upregulated (q<0.05)</italic></td></tr><tr><td align="left" valign="top" charoff="50"> <italic><bold>Ccl5</bold></italic></td><td align="left" valign="top" charoff="50"><bold>Chemokine (C-Cmotif) ligand 5</bold></td><td align="center" valign="top" charoff="50"><bold>8.6</bold></td><td align="center" valign="top" charoff="50"><bold>0.0014</bold></td></tr><tr><td align="left" valign="top" charoff="50"> <italic><bold>Fxyd5</bold></italic></td><td align="left" valign="top" charoff="50"><bold>FXYD domain-containing ion transport regulator 5</bold></td><td align="center" valign="top" charoff="50"><bold>3.1</bold></td><td align="center" valign="top" charoff="50"><bold>2.9e−5</bold></td></tr><tr><td align="left" valign="top" charoff="50"> <italic><bold>Wnt10a</bold></italic></td><td align="left" valign="top" charoff="50"><bold>Wingless related MMTV integration site 10a</bold></td><td align="center" valign="top" charoff="50"><bold>3.1</bold></td><td align="center" valign="top" charoff="50"><bold>4.9e−7</bold></td></tr><tr><td align="left" valign="top" charoff="50"> <italic><bold>Fah</bold></italic></td><td align="left" valign="top" charoff="50"><bold>Fumarylacetoacetate hydrolase</bold></td><td align="center" valign="top" charoff="50"><bold>2.6</bold></td><td align="center" valign="top" charoff="50"><bold>0.0014</bold></td></tr><tr><td align="left" valign="top" charoff="50"> <italic><bold>Slfn2</bold></italic></td><td align="left" valign="top" charoff="50"><bold>Schlafen 2</bold></td><td align="center" valign="top" charoff="50"><bold>2.5</bold></td><td align="center" valign="top" charoff="50"><bold>0.0130</bold></td></tr><tr><td align="left" valign="top" charoff="50"> <italic><bold>Irf8</bold></italic></td><td align="left" valign="top" charoff="50"><bold>Interferon regulatory factor 8</bold></td><td align="center" valign="top" charoff="50"><bold>2.5</bold></td><td align="center" valign="top" charoff="50"><bold>0.0095</bold></td></tr><tr><td align="left" valign="top" charoff="50"> <italic><bold>Siggir</bold></italic></td><td align="left" valign="top" charoff="50"><bold>Single immunoglobulin and toll-interleukin 1 receptor TIR domain</bold></td><td align="center" valign="top" charoff="50"><bold>2.5</bold></td><td align="center" valign="top" charoff="50"><bold>0.002</bold></td></tr><tr><td align="left" valign="top" charoff="50"> <italic><bold>Serpinc1</bold></italic></td><td align="left" valign="top" charoff="50"><bold>Serine (or cystein) peptidase inhibitor, clade C, member 1</bold></td><td align="center" valign="top" charoff="50"><bold>2.4</bold></td><td align="center" valign="top" charoff="50"><bold>0.02</bold></td></tr><tr><td align="left" valign="top" charoff="50"> <italic><bold>Bhlhe40</bold></italic></td><td align="left" valign="top" charoff="50"><bold>Basic helix-loop-helix family, member e40</bold></td><td align="center" valign="top" charoff="50"><bold>2.3</bold></td><td align="center" valign="top" charoff="50"><bold>0.049</bold></td></tr><tr><td align="left" valign="top" charoff="50"> <italic><bold>Grap</bold></italic></td><td align="left" valign="top" charoff="50"><bold>GRB2-related adaptor protein</bold></td><td align="center" valign="top" charoff="50"><bold>2.2</bold></td><td align="center" valign="top" charoff="50"><bold>0.017</bold></td></tr><tr><td align="left" valign="top" charoff="50"> <italic><bold>Ctla4</bold></italic></td><td align="left" valign="top" charoff="50"><bold>Cytotoxic T-lymphocyte-associated protein 4</bold></td><td align="center" valign="top" charoff="50"><bold>2.2</bold></td><td align="center" valign="top" charoff="50"><bold>0.047</bold></td></tr><tr><td align="left" valign="top" charoff="50"> <italic><bold>Lsp1</bold></italic></td><td align="left" valign="top" charoff="50"><bold>Lymphocyte specific 1</bold></td><td align="center" valign="top" charoff="50"><bold>2.2</bold></td><td align="center" valign="top" charoff="50"><bold>0.015</bold></td></tr><tr><td align="left" valign="top" charoff="50"> <italic><bold>Ptprcap</bold></italic></td><td align="left" valign="top" charoff="50"><bold>Protein tyrosine phosphatase receptor type C-associated protein</bold></td><td align="center" valign="top" charoff="50"><bold>2.1</bold></td><td align="center" valign="top" charoff="50"><bold>0.037</bold></td></tr><tr><td align="left" valign="top" charoff="50"> <italic><bold>Srgn</bold></italic></td><td align="left" valign="top" charoff="50"><bold>Serglycin</bold></td><td align="center" valign="top" charoff="50"><bold>2.1</bold></td><td align="center" valign="top" charoff="50"><bold>6.7e−8</bold></td></tr><tr><td align="left" valign="top" charoff="50"> <italic><bold>Gpnmb</bold></italic></td><td align="left" valign="top" charoff="50"><bold>Glycoprotein (transmembrane) nmb</bold></td><td align="center" valign="top" charoff="50"><bold>2.1</bold></td><td align="center" valign="top" charoff="50"><bold>0.042</bold></td></tr><tr><td align="left" valign="top" charoff="50"> <italic><bold>Ddt</bold></italic></td><td align="left" valign="top" charoff="50"><bold>D-dopachrome tautomerase</bold></td><td align="center" valign="top" charoff="50"><bold>2</bold></td><td align="center" valign="top" charoff="50"><bold>9.3e−4</bold></td></tr><tr><td align="left" valign="top" charoff="50"> <italic><bold>Endod1</bold></italic></td><td align="left" valign="top" charoff="50"><bold>Endonuclease domain-containing 1</bold></td><td align="center" valign="top" charoff="50"><bold>2</bold></td><td align="center" valign="top" charoff="50"><bold>0.015</bold></td></tr><tr><td align="left" valign="top" charoff="50"> <italic><bold>Tg</bold></italic></td><td align="left" valign="top" charoff="50"><bold>Thyroglobulin</bold></td><td align="center" valign="top" charoff="50"><bold>2</bold></td><td align="center" valign="top" charoff="50"><bold>0.042</bold></td></tr><tr><td align="left" valign="top" charoff="50"> <italic><bold>Casp4</bold></italic></td><td align="left" valign="top" charoff="50"><bold>Caspase 4</bold></td><td align="center" valign="top" charoff="50"><bold>2</bold></td><td align="center" valign="top" charoff="50"><bold>0.018</bold></td></tr><tr><td align="left" valign="top" charoff="50"> </td><td align="left" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td></tr><tr><td colspan="4" align="center" valign="top" charoff="50"><italic>Differentially expressed genes, downregulated (q<0.05)</italic></td></tr><tr><td align="left" valign="top" charoff="50"> <italic><bold>Reln</bold></italic></td><td align="left" valign="top" charoff="50"><bold>reelin</bold></td><td align="center" valign="top" charoff="50"><bold>0.47</bold></td><td align="center" valign="top" charoff="50"><bold>0.018</bold></td></tr><tr><td align="left" valign="top" charoff="50"> <italic>Negr1</italic></td><td align="left" valign="top" charoff="50">Neuronal growth regulator 1</td><td align="center" valign="top" charoff="50">0.51</td><td align="center" valign="top" charoff="50">0.022</td></tr><tr><td align="left" valign="top" charoff="50"> <italic>Plekhm3</italic></td><td align="left" valign="top" charoff="50">Pleckstrin homology domain-containing family M, member 3</td><td align="center" valign="top" charoff="50">0.54</td><td align="center" valign="top" charoff="50">0.017</td></tr><tr><td align="left" valign="top" charoff="50"> <italic>Pfkm</italic></td><td align="left" valign="top" charoff="50">Phosphofructokinase, muscle</td><td align="center" valign="top" charoff="50">0.55</td><td align="center" valign="top" charoff="50">0.027</td></tr><tr><td align="left" valign="top" charoff="50"> <italic>C1qtnf1</italic></td><td align="left" valign="top" charoff="50">Complement C1q tumour necrosis factor-related protein 1</td><td align="center" valign="top" charoff="50">0.55</td><td align="center" valign="top" charoff="50">0.049</td></tr><tr><td align="left" valign="top" charoff="50"> <italic>Gpr155</italic></td><td align="left" valign="top" charoff="50">G protein-coupled receptor 155</td><td align="center" valign="top" charoff="50">0.56</td><td align="center" valign="top" charoff="50">0.0012</td></tr><tr><td align="left" valign="top" charoff="50"> <italic>Upb1</italic></td><td align="left" valign="top" charoff="50">Ureidopropionase, beta</td><td align="center" valign="top" charoff="50">0.58</td><td align="center" valign="top" charoff="50">0.038</td></tr><tr><td align="left" valign="top" charoff="50"> <italic>Pgam2</italic></td><td align="left" valign="top" charoff="50">Phosphoglycerate mutase 2</td><td align="center" valign="top" charoff="50">0.60</td><td align="center" valign="top" charoff="50">0.034</td></tr><tr><td align="left" valign="top" charoff="50"> <italic>Dhx33</italic></td><td align="left" valign="top" charoff="50">DEAH box polypeptide 33</td><td align="center" valign="top" charoff="50">0.60</td><td align="center" valign="top" charoff="50">0.021</td></tr><tr><td align="left" valign="top" charoff="50"> <italic>Tnfrsf17</italic></td><td align="left" valign="top" charoff="50">Tumour necrosis factor receptor superfamily</td><td align="center" valign="top" charoff="50">0.60</td><td align="center" valign="top" charoff="50">0.002</td></tr></tbody></table><table-wrap-foot><fn id="t1-fn1"><p>FC, fold change.</p></fn><fn id="t1-fn2"><p>Only genes with a fold change superior or equal to 2 (for upregulated genes) or with a fold change inferior or equal to 0.60 (/1.7) (for downregulated genes) have been included in the table. The 20 most significantly modulated genes (highest absolute fold change) in the antigen-stimulated plasma cells group are shown in bold characters. They constitute the study group that has been analysed by MGSA (<xref ref-type="table" rid="t2">Table 2</xref>).</p></fn></table-wrap-foot></table-wrap><table-wrap position="float" id="t2"><label>Table 2</label><caption><title>Gene Ontology terms most strongly associated with the 20 most significantly modulated genes in the antigen-stimulated IgM<sup>+</sup> plasma cell group.</title></caption><table frame="hsides" rules="groups" border="1"><colgroup><col align="left"></col><col align="left"></col><col align="center"></col><col align="center"></col><col align="left"></col><col align="center"></col></colgroup><thead valign="bottom"><tr><th align="left" valign="top" charoff="50"> </th><th align="left" valign="top" charoff="50"><bold>Description</bold></th><th align="center" valign="top" charoff="50"><bold>Identity</bold></th><th align="center" valign="top" charoff="50"><bold>Freq.</bold></th><th align="left" valign="top" charoff="50"><bold>Genes</bold></th><th align="center" valign="top" charoff="50"><bold>Nb</bold></th></tr></thead><tbody valign="top"><tr><td align="left" valign="top" charoff="50"><bold>1</bold></td><td align="left" valign="top" charoff="50"><bold>Regulation of cytokine production</bold></td><td align="center" valign="top" charoff="50"><bold>GO:0001817</bold></td><td align="center" valign="top" charoff="50"><bold>0.32</bold></td><td align="left" valign="top" charoff="50"><italic><bold>Ccl5, Irf8, Siggir, Srgn, Casp 4</bold></italic></td><td align="center" valign="top" charoff="50"><bold>349</bold></td></tr><tr><td align="left" valign="top" charoff="50"><bold>2</bold></td><td align="left" valign="top" charoff="50"><bold>Cytokine production</bold></td><td align="center" valign="top" charoff="50"><bold>GO:0001816</bold></td><td align="center" valign="top" charoff="50"><bold>0.21</bold></td><td align="left" valign="top" charoff="50"><italic><bold>Ccl5, Irf8, Siggir, Srgn, Casp 4</bold></italic></td><td align="center" valign="top" charoff="50"><bold>391</bold></td></tr><tr><td align="left" valign="top" charoff="50">3</td><td align="left" valign="top" charoff="50">Thyroid hormone metabolic process</td><td align="center" valign="top" charoff="50">GO:0042403</td><td align="center" valign="top" charoff="50">0.12</td><td align="left" valign="top" charoff="50"><italic>Reln, Tg</italic></td><td align="center" valign="top" charoff="50">15</td></tr><tr><td align="left" valign="top" charoff="50">4</td><td align="left" valign="top" charoff="50">Cellular amino acid metabolic process</td><td align="center" valign="top" charoff="50">GO:0006520</td><td align="center" valign="top" charoff="50">0.11</td><td align="left" valign="top" charoff="50"><italic>Fah, Reln, Tg</italic></td><td align="center" valign="top" charoff="50">213</td></tr><tr><td align="left" valign="top" charoff="50">5</td><td align="left" valign="top" charoff="50">Phenol-containing compound metabolic process</td><td align="center" valign="top" charoff="50">GO:0018958</td><td align="center" valign="top" charoff="50">0.057</td><td align="left" valign="top" charoff="50"><italic>Reln, Tg</italic></td><td align="center" valign="top" charoff="50">59</td></tr><tr><td align="left" valign="top" charoff="50">6</td><td align="left" valign="top" charoff="50">Negative regulation of sequence-specific DNA binding transcription factor activity</td><td align="center" valign="top" charoff="50">GO:0043433</td><td align="center" valign="top" charoff="50">0.044</td><td align="left" valign="top" charoff="50"><italic>Sigirr, Bhlhe40</italic></td><td align="center" valign="top" charoff="50">114</td></tr><tr><td align="left" valign="top" charoff="50">7</td><td align="left" valign="top" charoff="50">Cytokine secretion</td><td align="center" valign="top" charoff="50">GO:0050663</td><td align="center" valign="top" charoff="50">0.042</td><td align="left" valign="top" charoff="50"><italic>Srgn, Casp4</italic></td><td align="center" valign="top" charoff="50">86</td></tr><tr><td align="left" valign="top" charoff="50">8</td><td align="left" valign="top" charoff="50">Regulation of cytokine secretion</td><td align="center" valign="top" charoff="50">GO:0050707</td><td align="center" valign="top" charoff="50">0.042</td><td align="left" valign="top" charoff="50"><italic>Srgn, Casp4</italic></td><td align="center" valign="top" charoff="50">75</td></tr><tr><td align="left" valign="top" charoff="50">9</td><td align="left" valign="top" charoff="50">Entrainment of circadian clock by photoperiod</td><td align="center" valign="top" charoff="50">GO:0043153</td><td align="center" valign="top" charoff="50">0.039</td><td align="left" valign="top" charoff="50"><italic>Bhlhe40</italic></td><td align="center" valign="top" charoff="50">5</td></tr></tbody></table><table-wrap-foot><fn id="t2-fn1"><p>Freq. is the frequency with which the gene set is activated in the algorithm; Nb, numbers of genes in the reference set.</p></fn><fn id="t2-fn2"><p>Data have been analysed with the MGSA (Model-based Gene Set Analysis) algorithm. The study gene set encompasses the 20 genes with the highest absolute fold change (and adjusted <italic>P</italic> value<0.05) in the antigen-stimulated plasma cell group. MGSA infers the ‘active' gene sets of the experiment, among all considered gene sets, given the actual genes observed as differentially expressed. The column entitled ‘genes' details the genes that are shared by the study gene set and by the gene set defining the GO term. Bold identifies biological processes that are further discussed in the manuscript.</p></fn></table-wrap-foot></table-wrap></floats-group></pmc><affiliations><list><country><li>Allemagne</li><li>Australie</li><li>France</li></country></list><tree><country name="France"><noRegion><name sortKey="Blanc, Pascal" sort="Blanc, Pascal" uniqKey="Blanc P" first="Pascal" last="Blanc">Pascal Blanc</name></noRegion><name sortKey="Barthly, Lucas" sort="Barthly, Lucas" uniqKey="Barthly L" first="Lucas" last="Barthly">Lucas Barthly</name><name sortKey="Buffat, Laurent" sort="Buffat, Laurent" uniqKey="Buffat L" first="Laurent" last="Buffat">Laurent Buffat</name><name sortKey="Colisson, Renaud" sort="Colisson, Renaud" uniqKey="Colisson R" first="Renaud" last="Colisson">Renaud Colisson</name><name sortKey="De Bernard, Simon" sort="De Bernard, Simon" uniqKey="De Bernard S" first="Simon" last="De Bernard">Simon De Bernard</name><name sortKey="Defrance, Thierry" sort="Defrance, Thierry" uniqKey="Defrance T" first="Thierry" last="Defrance">Thierry Defrance</name><name sortKey="Dussurgey, Sebastien" sort="Dussurgey, Sebastien" uniqKey="Dussurgey S" first="Sébastien" last="Dussurgey">Sébastien Dussurgey</name><name sortKey="Fest, Thierry" sort="Fest, Thierry" uniqKey="Fest T" first="Thierry" last="Fest">Thierry Fest</name><name sortKey="Fest, Thierry" sort="Fest, Thierry" uniqKey="Fest T" first="Thierry" last="Fest">Thierry Fest</name><name sortKey="Fest, Thierry" sort="Fest, Thierry" uniqKey="Fest T" first="Thierry" last="Fest">Thierry Fest</name><name sortKey="Genestier, Laurent" sort="Genestier, Laurent" uniqKey="Genestier L" first="Laurent" last="Genestier">Laurent Genestier</name><name sortKey="Jagot, Ferdinand" sort="Jagot, Ferdinand" uniqKey="Jagot F" first="Ferdinand" last="Jagot">Ferdinand Jagot</name><name sortKey="Mondiere, Paul" sort="Mondiere, Paul" uniqKey="Mondiere P" first="Paul" last="Mondière">Paul Mondière</name><name sortKey="Moro Sibilot, Ludovic" sort="Moro Sibilot, Ludovic" uniqKey="Moro Sibilot L" first="Ludovic" last="Moro-Sibilot">Ludovic Moro-Sibilot</name><name sortKey="Sicard, Antoine" sort="Sicard, Antoine" uniqKey="Sicard A" first="Antoine" last="Sicard">Antoine Sicard</name><name sortKey="Taillardet, Morgan" sort="Taillardet, Morgan" uniqKey="Taillardet M" first="Morgan" last="Taillardet">Morgan Taillardet</name><name sortKey="Thaunat, Olivier" sort="Thaunat, Olivier" uniqKey="Thaunat O" first="Olivier" last="Thaunat">Olivier Thaunat</name><name sortKey="This, Sebastien" sort="This, Sebastien" uniqKey="This S" first="Sébastien" last="This">Sébastien This</name></country><country name="Allemagne"><noRegion><name sortKey="Hobeika, Elias" sort="Hobeika, Elias" uniqKey="Hobeika E" first="Elias" last="Hobeika">Elias Hobeika</name></noRegion></country><country name="Australie"><noRegion><name sortKey="Nutt, Stephen L" sort="Nutt, Stephen L" uniqKey="Nutt S" first="Stephen L." last="Nutt">Stephen L. Nutt</name></noRegion><name sortKey="Nutt, Stephen L" sort="Nutt, Stephen L" uniqKey="Nutt S" first="Stephen L." last="Nutt">Stephen L. Nutt</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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