The development and survival but not function of follicular B cells is dependent on IL-7Rα Tyr449 signaling
IL-7 is a critical cytokine for lymphocyte development. Recent work has highlighted critical roles for IL-7 signaling in mature T cell homeostasis and function, but its role in B cells is less well characterized. Using a knock-in mouse possessing a Tyr to Phe mutation at position 449 (IL-7Rα(449F/44...
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| description | IL-7 is a critical cytokine for lymphocyte development. Recent work has highlighted critical roles for IL-7 signaling in mature T cell homeostasis and function, but its role in B cells is less well characterized. Using a knock-in mouse possessing a Tyr to Phe mutation at position 449 (IL-7Rα(449F/449F) mice) within the cytoplasmic SH2-binding motif of IL-7Rα, we evaluated the role of IL-7Rα Y449 motif in spleen B cells. IL-7Rα(449F/449F) mice had reduced numbers and increased death of follicular B cells compared to WT, but had significantly more follicular cells than IL-7Rα(-/-). The death of IL-7Rα(449F/449F) follicular cells was not due to a failure to respond to BAFF or lower levels of BAFF, a critical B cell survival factor. Marginal zone B cells were unaffected by the IL-7Rα(449F/449F) mutation. Any role for TSLP was ruled out, as TSLPR(-/-) mice had an identical B cell phenotype to wild-type mice. Bone marrow chimeras and the absence of IL-7Rα on B cells suggested that IL-7 did not directly regulate mature B cells, but that an IL-7-responsive cell was influencing B cells. IL-7 was also critical at the checkpoint between the T1 and T2 stages in the spleen. IL-7Rα(-/-) mice fail to develop T2 cells, but IL-7Rα(449F/449F) show a reduction compared to WT but not complete absence of T2 cells. We also tested the functional responses of IL-7Rα(449F/449F) to antigens and infection and found no difference in antibody responses to T-dependent or T-independent antigens, or to Influenza/A. IL-7 was important for generation of antibody responses to the intestinal worm H. polygyrus and for naive levels of IgA. Taken together, this suggests that IL-7 regulates follicular B cell numbers and survival in a cell-extrinsic manner, via a bone-marrow derived cell, but is not critical for antibody production outside the gut. |
| doi_str_mv | 10.1371/journal.pone.0088771 |
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Recent work has highlighted critical roles for IL-7 signaling in mature T cell homeostasis and function, but its role in B cells is less well characterized. Using a knock-in mouse possessing a Tyr to Phe mutation at position 449 (IL-7Rα(449F/449F) mice) within the cytoplasmic SH2-binding motif of IL-7Rα, we evaluated the role of IL-7Rα Y449 motif in spleen B cells. IL-7Rα(449F/449F) mice had reduced numbers and increased death of follicular B cells compared to WT, but had significantly more follicular cells than IL-7Rα(-/-). The death of IL-7Rα(449F/449F) follicular cells was not due to a failure to respond to BAFF or lower levels of BAFF, a critical B cell survival factor. Marginal zone B cells were unaffected by the IL-7Rα(449F/449F) mutation. Any role for TSLP was ruled out, as TSLPR(-/-) mice had an identical B cell phenotype to wild-type mice. Bone marrow chimeras and the absence of IL-7Rα on B cells suggested that IL-7 did not directly regulate mature B cells, but that an IL-7-responsive cell was influencing B cells. IL-7 was also critical at the checkpoint between the T1 and T2 stages in the spleen. IL-7Rα(-/-) mice fail to develop T2 cells, but IL-7Rα(449F/449F) show a reduction compared to WT but not complete absence of T2 cells. We also tested the functional responses of IL-7Rα(449F/449F) to antigens and infection and found no difference in antibody responses to T-dependent or T-independent antigens, or to Influenza/A. IL-7 was important for generation of antibody responses to the intestinal worm H. polygyrus and for naive levels of IgA. Taken together, this suggests that IL-7 regulates follicular B cell numbers and survival in a cell-extrinsic manner, via a bone-marrow derived cell, but is not critical for antibody production outside the gut.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0088771</identifier><identifier>PMID: 24551160</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Amino Acid Substitution ; Animals ; Antibodies, Viral - blood ; Antigens ; Antigens, Viral - blood ; B-Cell Activating Factor - genetics ; B-Cell Activating Factor - immunology ; B-Lymphocytes - cytology ; B-Lymphocytes - immunology ; Biology ; BLyS protein ; Bone marrow ; Cell Survival ; Chimeras ; Cytokines ; Cytokines - genetics ; Cytokines - immunology ; Gene Expression Regulation ; Gene Knock-In Techniques ; Genotype & phenotype ; Homeostasis ; Immunoglobulin A ; Immunoglobulin G - blood ; Immunoglobulins ; Immunology ; Influenza ; Influenza A ; Influenza A virus - immunology ; Interleukin 7 ; Interleukin-7 - genetics ; Interleukin-7 - immunology ; Intestine ; Lymphocytes ; Lymphocytes B ; Lymphocytes T ; Medicine ; Mice ; Mice, Transgenic ; Mutation ; Protein Interaction Domains and Motifs ; Receptors, Interleukin-7 - deficiency ; Receptors, Interleukin-7 - genetics ; Receptors, Interleukin-7 - immunology ; Rodents ; Signal Transduction - immunology ; Signaling ; Spleen ; Spleen - cytology ; Spleen - immunology ; Studies ; Survival ; Survival factor ; Thymic stromal lymphopoietin</subject><ispartof>PloS one, 2014-02, Vol.9 (2), p.e88771</ispartof><rights>2014 Patton et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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Recent work has highlighted critical roles for IL-7 signaling in mature T cell homeostasis and function, but its role in B cells is less well characterized. Using a knock-in mouse possessing a Tyr to Phe mutation at position 449 (IL-7Rα(449F/449F) mice) within the cytoplasmic SH2-binding motif of IL-7Rα, we evaluated the role of IL-7Rα Y449 motif in spleen B cells. IL-7Rα(449F/449F) mice had reduced numbers and increased death of follicular B cells compared to WT, but had significantly more follicular cells than IL-7Rα(-/-). The death of IL-7Rα(449F/449F) follicular cells was not due to a failure to respond to BAFF or lower levels of BAFF, a critical B cell survival factor. Marginal zone B cells were unaffected by the IL-7Rα(449F/449F) mutation. Any role for TSLP was ruled out, as TSLPR(-/-) mice had an identical B cell phenotype to wild-type mice. 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blood</subject><subject>Immunoglobulins</subject><subject>Immunology</subject><subject>Influenza</subject><subject>Influenza A</subject><subject>Influenza A virus - immunology</subject><subject>Interleukin 7</subject><subject>Interleukin-7 - genetics</subject><subject>Interleukin-7 - immunology</subject><subject>Intestine</subject><subject>Lymphocytes</subject><subject>Lymphocytes B</subject><subject>Lymphocytes T</subject><subject>Medicine</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Mutation</subject><subject>Protein Interaction Domains and Motifs</subject><subject>Receptors, Interleukin-7 - deficiency</subject><subject>Receptors, Interleukin-7 - genetics</subject><subject>Receptors, Interleukin-7 - immunology</subject><subject>Rodents</subject><subject>Signal Transduction - immunology</subject><subject>Signaling</subject><subject>Spleen</subject><subject>Spleen - cytology</subject><subject>Spleen - immunology</subject><subject>Studies</subject><subject>Survival</subject><subject>Survival factor</subject><subject>Thymic stromal lymphopoietin</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNp1UtGOEyEUJUbj7lb_wCiJz1NhYBjmxUQ3rjZpYmLqM2HgTpeGQoWZJvtZ_ojfJLWzm90HnyDcc84993IQekPJkrKWftjFKQXtl4cYYEmIlG1Ln6FL2rG6EjVhzx_dL9BVzjtCGiaFeIkuat40lApyifzmFrCFI_h42EMYsQ4W5ykd3VF73E8jDnHEwxTM6GLAccBD9N6ZyeuEP2MD3mfscpE4QLAngYJarav2x5_feHOXOO9wdtti1IXtK_Ri0D7D6_lcoJ83XzbX36r196-r60_ryjS1GKvWMjpYKBYNZdJ2RNpmIERLVjPCbd1TA0Qy2gBlHEhnO0Fr1tWlwo0dgC3Qu7Puwces5kVlRTvJeBmd8IJYnRE26p06JLfX6U5F7dS_h5i2SqfRGQ9KDz1hRJCmFcClFh1waDrbi741QmpatD7O3aZ-D9aUJSTtn4g-rQR3q7bxqIplJssfLdD7WSDFXxPk8T-W-RllUsw5wfDQgRJ1SsQ9S50SoeZEFNrbx-4eSPcRYH8By4i0_Q</recordid><startdate>20140213</startdate><enddate>20140213</enddate><creator>Patton, Daniel T</creator><creator>Plumb, Adam W</creator><creator>Redpath, Stephen A</creator><creator>Osborne, Lisa C</creator><creator>Perona-Wright, Georgia</creator><creator>Abraham, Ninan</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20140213</creationdate><title>The development and survival but not function of follicular B cells is dependent on IL-7Rα Tyr449 signaling</title><author>Patton, Daniel T ; Plumb, Adam W ; Redpath, Stephen A ; Osborne, Lisa C ; Perona-Wright, Georgia ; Abraham, Ninan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c526t-7d31fde551c138d908d5f00a832304d2b1ce08315e134e09d9612392d2b4cdfe3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Amino Acid Substitution</topic><topic>Animals</topic><topic>Antibodies, Viral - blood</topic><topic>Antigens</topic><topic>Antigens, Viral - blood</topic><topic>B-Cell Activating Factor - genetics</topic><topic>B-Cell Activating Factor - immunology</topic><topic>B-Lymphocytes - cytology</topic><topic>B-Lymphocytes - immunology</topic><topic>Biology</topic><topic>BLyS protein</topic><topic>Bone marrow</topic><topic>Cell Survival</topic><topic>Chimeras</topic><topic>Cytokines</topic><topic>Cytokines - genetics</topic><topic>Cytokines - immunology</topic><topic>Gene Expression Regulation</topic><topic>Gene Knock-In Techniques</topic><topic>Genotype & phenotype</topic><topic>Homeostasis</topic><topic>Immunoglobulin A</topic><topic>Immunoglobulin G - blood</topic><topic>Immunoglobulins</topic><topic>Immunology</topic><topic>Influenza</topic><topic>Influenza A</topic><topic>Influenza A virus - immunology</topic><topic>Interleukin 7</topic><topic>Interleukin-7 - genetics</topic><topic>Interleukin-7 - immunology</topic><topic>Intestine</topic><topic>Lymphocytes</topic><topic>Lymphocytes B</topic><topic>Lymphocytes T</topic><topic>Medicine</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Mutation</topic><topic>Protein Interaction Domains and Motifs</topic><topic>Receptors, Interleukin-7 - 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Recent work has highlighted critical roles for IL-7 signaling in mature T cell homeostasis and function, but its role in B cells is less well characterized. Using a knock-in mouse possessing a Tyr to Phe mutation at position 449 (IL-7Rα(449F/449F) mice) within the cytoplasmic SH2-binding motif of IL-7Rα, we evaluated the role of IL-7Rα Y449 motif in spleen B cells. IL-7Rα(449F/449F) mice had reduced numbers and increased death of follicular B cells compared to WT, but had significantly more follicular cells than IL-7Rα(-/-). The death of IL-7Rα(449F/449F) follicular cells was not due to a failure to respond to BAFF or lower levels of BAFF, a critical B cell survival factor. Marginal zone B cells were unaffected by the IL-7Rα(449F/449F) mutation. Any role for TSLP was ruled out, as TSLPR(-/-) mice had an identical B cell phenotype to wild-type mice. Bone marrow chimeras and the absence of IL-7Rα on B cells suggested that IL-7 did not directly regulate mature B cells, but that an IL-7-responsive cell was influencing B cells. IL-7 was also critical at the checkpoint between the T1 and T2 stages in the spleen. IL-7Rα(-/-) mice fail to develop T2 cells, but IL-7Rα(449F/449F) show a reduction compared to WT but not complete absence of T2 cells. We also tested the functional responses of IL-7Rα(449F/449F) to antigens and infection and found no difference in antibody responses to T-dependent or T-independent antigens, or to Influenza/A. IL-7 was important for generation of antibody responses to the intestinal worm H. polygyrus and for naive levels of IgA. Taken together, this suggests that IL-7 regulates follicular B cell numbers and survival in a cell-extrinsic manner, via a bone-marrow derived cell, but is not critical for antibody production outside the gut.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24551160</pmid><doi>10.1371/journal.pone.0088771</doi><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_1983424504 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS); PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Amino Acid Substitution Animals Antibodies, Viral - blood Antigens Antigens, Viral - blood B-Cell Activating Factor - genetics B-Cell Activating Factor - immunology B-Lymphocytes - cytology B-Lymphocytes - immunology Biology BLyS protein Bone marrow Cell Survival Chimeras Cytokines Cytokines - genetics Cytokines - immunology Gene Expression Regulation Gene Knock-In Techniques Genotype & phenotype Homeostasis Immunoglobulin A Immunoglobulin G - blood Immunoglobulins Immunology Influenza Influenza A Influenza A virus - immunology Interleukin 7 Interleukin-7 - genetics Interleukin-7 - immunology Intestine Lymphocytes Lymphocytes B Lymphocytes T Medicine Mice Mice, Transgenic Mutation Protein Interaction Domains and Motifs Receptors, Interleukin-7 - deficiency Receptors, Interleukin-7 - genetics Receptors, Interleukin-7 - immunology Rodents Signal Transduction - immunology Signaling Spleen Spleen - cytology Spleen - immunology Studies Survival Survival factor Thymic stromal lymphopoietin |
| title | The development and survival but not function of follicular B cells is dependent on IL-7Rα Tyr449 signaling |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-22T18%3A57%3A05IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=The%20development%20and%20survival%20but%20not%20function%20of%20follicular%20B%20cells%20is%20dependent%20on%20IL-7R%CE%B1%20Tyr449%20signaling&rft.jtitle=PloS%20one&rft.au=Patton,%20Daniel%20T&rft.date=2014-02-13&rft.volume=9&rft.issue=2&rft.spage=e88771&rft.pages=e88771-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0088771&rft_dat=%3Cproquest_plos_%3E1983424504%3C/proquest_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1983424504&rft_id=info:pmid/24551160&rft_doaj_id=oai_doaj_org_article_afb03060576e48a69e4e59db6b7c68a1&rfr_iscdi=true |