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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">000472</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000472</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>
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