Signal inhibition by the dual-specific phosphatase 4 impairs T cell-dependent B-cell responses with age
Identifieur interne : 000732 ( Pmc/Corpus ); précédent : 000731; suivant : 000733Signal inhibition by the dual-specific phosphatase 4 impairs T cell-dependent B-cell responses with age
Auteurs : Mingcan Yu ; Guangjin Li ; Won-Woo Lee ; Ming Yuan ; Dapeng Cui ; Cornelia M. Weyand ; Jörg J. GoronzySource :
- Proceedings of the National Academy of Sciences of the United States of America [ 0027-8424 ] ; 2012.
Abstract
T cell-dependent B-cell responses decline with age, suggesting defective CD4 T-cell function. CD4 memory T cells from individuals older than 65 y displayed increased and sustained transcription of the dual-specific phosphatase 4 (DUSP4) that shortened expression of CD40-ligand (CD40L) and inducible T-cell costimulator (ICOS) (both
Url:
DOI: 10.1073/pnas.1109797109
PubMed: 22434910
PubMed Central: 3326453
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Signal inhibition by the dual-specific phosphatase 4 impairs T cell-dependent B-cell responses with age</title><author><name sortKey="Yu, Mingcan" sort="Yu, Mingcan" uniqKey="Yu M" first="Mingcan" last="Yu">Mingcan Yu</name><affiliation><nlm:aff id="aff1">Department of Medicine,<institution>Stanford University School of Medicine</institution>, Stanford,<addr-line>CA</addr-line> 94305;</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Department of Medicine,<institution>Palo Alto Department of Veterans Affairs Health Care System</institution>, Palo Alto,<addr-line>CA</addr-line> 94304;</nlm:aff></affiliation></author><author><name sortKey="Li, Guangjin" sort="Li, Guangjin" uniqKey="Li G" first="Guangjin" last="Li">Guangjin Li</name><affiliation><nlm:aff id="aff1">Department of Medicine,<institution>Stanford University School of Medicine</institution>, Stanford,<addr-line>CA</addr-line> 94305;</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Department of Medicine,<institution>Palo Alto Department of Veterans Affairs Health Care System</institution>, Palo Alto,<addr-line>CA</addr-line> 94304;</nlm:aff></affiliation></author><author><name sortKey="Lee, Won Woo" sort="Lee, Won Woo" uniqKey="Lee W" first="Won-Woo" last="Lee">Won-Woo Lee</name><affiliation><nlm:aff id="aff3">Department of Microbiology and Immunology,<institution>Seoul National University College of Medicine</institution>, Seoul 110-799,<country>South Korea</country>;</nlm:aff></affiliation></author><author><name sortKey="Yuan, Ming" sort="Yuan, Ming" uniqKey="Yuan M" first="Ming" last="Yuan">Ming Yuan</name><affiliation><nlm:aff wicri:cut="; and" id="aff4">School of Industrial and Systems Engineering,<institution>Georgia Institute of Technology</institution>, Atlanta,<addr-line>GA</addr-line> 30332</nlm:aff></affiliation></author><author><name sortKey="Cui, Dapeng" sort="Cui, Dapeng" uniqKey="Cui D" first="Dapeng" last="Cui">Dapeng Cui</name><affiliation><nlm:aff id="aff5">Lowance Center for Human Immunology,<institution>Emory University</institution>, Atlanta,<addr-line>GA</addr-line> 30322</nlm:aff></affiliation></author><author><name sortKey="Weyand, Cornelia M" sort="Weyand, Cornelia M" uniqKey="Weyand C" first="Cornelia M." last="Weyand">Cornelia M. Weyand</name><affiliation><nlm:aff id="aff1">Department of Medicine,<institution>Stanford University School of Medicine</institution>, Stanford,<addr-line>CA</addr-line> 94305;</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Department of Medicine,<institution>Palo Alto Department of Veterans Affairs Health Care System</institution>, Palo Alto,<addr-line>CA</addr-line> 94304;</nlm:aff></affiliation></author><author><name sortKey="Goronzy, Jorg J" sort="Goronzy, Jorg J" uniqKey="Goronzy J" first="Jörg J." last="Goronzy">Jörg J. Goronzy</name><affiliation><nlm:aff id="aff1">Department of Medicine,<institution>Stanford University School of Medicine</institution>, Stanford,<addr-line>CA</addr-line> 94305;</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Department of Medicine,<institution>Palo Alto Department of Veterans Affairs Health Care System</institution>, Palo Alto,<addr-line>CA</addr-line> 94304;</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">22434910</idno><idno type="pmc">3326453</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3326453</idno><idno type="RBID">PMC:3326453</idno><idno type="doi">10.1073/pnas.1109797109</idno><date when="2012">2012</date><idno type="wicri:Area/Pmc/Corpus">000732</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000732</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Signal inhibition by the dual-specific phosphatase 4 impairs T cell-dependent B-cell responses with age</title><author><name sortKey="Yu, Mingcan" sort="Yu, Mingcan" uniqKey="Yu M" first="Mingcan" last="Yu">Mingcan Yu</name><affiliation><nlm:aff id="aff1">Department of Medicine,<institution>Stanford University School of Medicine</institution>, Stanford,<addr-line>CA</addr-line> 94305;</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Department of Medicine,<institution>Palo Alto Department of Veterans Affairs Health Care System</institution>, Palo Alto,<addr-line>CA</addr-line> 94304;</nlm:aff></affiliation></author><author><name sortKey="Li, Guangjin" sort="Li, Guangjin" uniqKey="Li G" first="Guangjin" last="Li">Guangjin Li</name><affiliation><nlm:aff id="aff1">Department of Medicine,<institution>Stanford University School of Medicine</institution>, Stanford,<addr-line>CA</addr-line> 94305;</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Department of Medicine,<institution>Palo Alto Department of Veterans Affairs Health Care System</institution>, Palo Alto,<addr-line>CA</addr-line> 94304;</nlm:aff></affiliation></author><author><name sortKey="Lee, Won Woo" sort="Lee, Won Woo" uniqKey="Lee W" first="Won-Woo" last="Lee">Won-Woo Lee</name><affiliation><nlm:aff id="aff3">Department of Microbiology and Immunology,<institution>Seoul National University College of Medicine</institution>, Seoul 110-799,<country>South Korea</country>;</nlm:aff></affiliation></author><author><name sortKey="Yuan, Ming" sort="Yuan, Ming" uniqKey="Yuan M" first="Ming" last="Yuan">Ming Yuan</name><affiliation><nlm:aff wicri:cut="; and" id="aff4">School of Industrial and Systems Engineering,<institution>Georgia Institute of Technology</institution>, Atlanta,<addr-line>GA</addr-line> 30332</nlm:aff></affiliation></author><author><name sortKey="Cui, Dapeng" sort="Cui, Dapeng" uniqKey="Cui D" first="Dapeng" last="Cui">Dapeng Cui</name><affiliation><nlm:aff id="aff5">Lowance Center for Human Immunology,<institution>Emory University</institution>, Atlanta,<addr-line>GA</addr-line> 30322</nlm:aff></affiliation></author><author><name sortKey="Weyand, Cornelia M" sort="Weyand, Cornelia M" uniqKey="Weyand C" first="Cornelia M." last="Weyand">Cornelia M. Weyand</name><affiliation><nlm:aff id="aff1">Department of Medicine,<institution>Stanford University School of Medicine</institution>, Stanford,<addr-line>CA</addr-line> 94305;</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Department of Medicine,<institution>Palo Alto Department of Veterans Affairs Health Care System</institution>, Palo Alto,<addr-line>CA</addr-line> 94304;</nlm:aff></affiliation></author><author><name sortKey="Goronzy, Jorg J" sort="Goronzy, Jorg J" uniqKey="Goronzy J" first="Jörg J." last="Goronzy">Jörg J. Goronzy</name><affiliation><nlm:aff id="aff1">Department of Medicine,<institution>Stanford University School of Medicine</institution>, Stanford,<addr-line>CA</addr-line> 94305;</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Department of Medicine,<institution>Palo Alto Department of Veterans Affairs Health Care System</institution>, Palo Alto,<addr-line>CA</addr-line> 94304;</nlm:aff></affiliation></author></analytic><series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title><idno type="ISSN">0027-8424</idno><idno type="eISSN">1091-6490</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>T cell-dependent B-cell responses decline with age, suggesting defective CD4 T-cell function. CD4 memory T cells from individuals older than 65 y displayed increased and sustained transcription of the dual-specific phosphatase 4 (DUSP4) that shortened expression of CD40-ligand (CD40L) and inducible T-cell costimulator (ICOS) (both <italic>P</italic> < 0.001) and decreased production of IL-4, IL-17A, and IL-21 (all <italic>P</italic> < 0.001) after in vitro activation. In vivo after influenza vaccination, activated CD4 T cells from elderly individuals had increased DUSP4 transcription (<italic>P</italic> = 0.002), which inversely correlated with the expression of CD40L (<italic>r</italic> = 0.65, <italic>P</italic> = 0.002), ICOS (<italic>r</italic> = 0.57, <italic>P</italic> = 0.008), and IL-4 (<italic>r</italic> = 0.66, <italic>P</italic> = 0.001). In CD4 KO mice reconstituted with <italic>DUSP4</italic> OT-II T cells, DUSP4 had a negative effect on the expansion of antigen-specific B cells (<italic>P</italic> = 0.003) and the production of ova-specific antibodies (<italic>P</italic> = 0.03) after immunization. Silencing of DUSP4 in memory CD4 T cells improved CD40L (<italic>P</italic> < 0.001), IL-4 (<italic>P</italic> = 0.007), and IL-21 (<italic>P</italic> = 0.04) expression significantly more in the elderly than young adults. Consequently, the ability of CD4 memory T cells to support B-cell differentiation that was impaired in the elderly (<italic>P</italic> = 0.004) was restored. Our data suggest that increased DUSP4 expression in activated T cells in the elderly in part accounts for defective adaptive immune responses.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Proc Natl Acad Sci U S A</journal-id><journal-id journal-id-type="iso-abbrev">Proc. Natl. Acad. Sci. U.S.A</journal-id><journal-id journal-id-type="hwp">pnas</journal-id><journal-id journal-id-type="pmc">pnas</journal-id><journal-id journal-id-type="publisher-id">PNAS</journal-id><journal-title-group><journal-title>Proceedings of the National Academy of Sciences of the United States of America</journal-title></journal-title-group><issn pub-type="ppub">0027-8424</issn><issn pub-type="epub">1091-6490</issn><publisher><publisher-name>National Academy of Sciences</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">22434910</article-id><article-id pub-id-type="pmc">3326453</article-id><article-id pub-id-type="publisher-id">201109797</article-id><article-id pub-id-type="doi">10.1073/pnas.1109797109</article-id><article-categories><subj-group subj-group-type="heading"><subject>PNAS Plus</subject></subj-group><subj-group subj-group-type="heading"><subject>Biological Sciences</subject><subj-group><subject>Immunology</subject></subj-group></subj-group><series-title>PNAS Plus</series-title></article-categories><title-group><article-title>Signal inhibition by the dual-specific phosphatase 4 impairs T cell-dependent B-cell responses with age</article-title><alt-title alt-title-type="short">DUSP4 signaling in T-cell aging</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Yu</surname><given-names>Mingcan</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Guangjin</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lee</surname><given-names>Won-Woo</given-names></name><xref ref-type="aff" rid="aff3"><sup>c</sup></xref></contrib><contrib contrib-type="author"><name><surname>Yuan</surname><given-names>Ming</given-names></name><xref ref-type="aff" rid="aff4"><sup>d</sup></xref></contrib><contrib contrib-type="author"><name><surname>Cui</surname><given-names>Dapeng</given-names></name><xref ref-type="aff" rid="aff5"><sup>e</sup></xref></contrib><contrib contrib-type="author"><name><surname>Weyand</surname><given-names>Cornelia M.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Goronzy</surname><given-names>Jörg J.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="aff" rid="aff2"><sup>b</sup></xref><xref ref-type="corresp" rid="cor1"><sup>1</sup></xref></contrib><aff id="aff1"><sup>a</sup>Department of Medicine,<institution>Stanford University School of Medicine</institution>, Stanford,<addr-line>CA</addr-line> 94305;</aff><aff id="aff2"><sup>b</sup>Department of Medicine,<institution>Palo Alto Department of Veterans Affairs Health Care System</institution>, Palo Alto,<addr-line>CA</addr-line> 94304;</aff><aff id="aff3"><sup>c</sup>Department of Microbiology and Immunology,<institution>Seoul National University College of Medicine</institution>, Seoul 110-799,<country>South Korea</country>;</aff><aff id="aff4"><sup>d</sup>School of Industrial and Systems Engineering,<institution>Georgia Institute of Technology</institution>, Atlanta,<addr-line>GA</addr-line> 30332; and</aff><aff id="aff5"><sup>e</sup>Lowance Center for Human Immunology,<institution>Emory University</institution>, Atlanta,<addr-line>GA</addr-line> 30322</aff></contrib-group><author-notes><corresp id="cor1"><sup>1</sup>To whom correspondence should be addressed. E-mail: <email>jgoronzy@stanford.edu</email>.</corresp><fn fn-type="edited-by"><p>Edited by Rino Rappuoli, Novartis Vaccines, Siena, Italy, and approved February 22, 2012 (received for review June 17, 2011)</p></fn><fn fn-type="con"><p>Author contributions: M. Yu, C.M.W., and J.J.G. designed research; M. Yu, G.L., W.-W.L., and D.C. performed research; M. Yu, G.L., W.-W.L., M. Yuan, C.M.W., and J.J.G. analyzed data; and M. Yu and J.J.G. wrote the paper.</p></fn><fn fn-type="conflict"><p>The authors declare no conflict of interest.</p></fn></author-notes><pub-date pub-type="ppub"><day>10</day><month>4</month><year>2012</year></pub-date><pub-date pub-type="epub"><day>20</day><month>3</month><year>2012</year></pub-date><volume>109</volume><issue>15</issue><fpage>E879</fpage><lpage>E888</lpage><page-range>E879–E888</page-range><self-uri content-type="pdf" xlink:type="simple" xlink:href="pnas.201109797.pdf"></self-uri><self-uri content-type="author-summary-pdf" xlink:type="simple" xlink:href="pnas.201109797_summary.pdf"></self-uri><abstract id="d34e215"><p>T cell-dependent B-cell responses decline with age, suggesting defective CD4 T-cell function. CD4 memory T cells from individuals older than 65 y displayed increased and sustained transcription of the dual-specific phosphatase 4 (DUSP4) that shortened expression of CD40-ligand (CD40L) and inducible T-cell costimulator (ICOS) (both <italic>P</italic> < 0.001) and decreased production of IL-4, IL-17A, and IL-21 (all <italic>P</italic> < 0.001) after in vitro activation. In vivo after influenza vaccination, activated CD4 T cells from elderly individuals had increased DUSP4 transcription (<italic>P</italic> = 0.002), which inversely correlated with the expression of CD40L (<italic>r</italic> = 0.65, <italic>P</italic> = 0.002), ICOS (<italic>r</italic> = 0.57, <italic>P</italic> = 0.008), and IL-4 (<italic>r</italic> = 0.66, <italic>P</italic> = 0.001). In CD4 KO mice reconstituted with <italic>DUSP4</italic> OT-II T cells, DUSP4 had a negative effect on the expansion of antigen-specific B cells (<italic>P</italic> = 0.003) and the production of ova-specific antibodies (<italic>P</italic> = 0.03) after immunization. Silencing of DUSP4 in memory CD4 T cells improved CD40L (<italic>P</italic> < 0.001), IL-4 (<italic>P</italic> = 0.007), and IL-21 (<italic>P</italic> = 0.04) expression significantly more in the elderly than young adults. Consequently, the ability of CD4 memory T cells to support B-cell differentiation that was impaired in the elderly (<italic>P</italic> = 0.004) was restored. Our data suggest that increased DUSP4 expression in activated T cells in the elderly in part accounts for defective adaptive immune responses.</p></abstract><kwd-group><kwd>immunosenescence</kwd><kwd>signaling</kwd><kwd>aging</kwd></kwd-group><custom-meta-group><custom-meta><meta-name>author-summary</meta-name><meta-value><xref ref-type="other" rid="author-summary"></xref></meta-value></custom-meta></custom-meta-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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