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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">The cytolytic molecules Fas ligand and TRAIL are required for murine thymic graft-versus-host disease</title>
<author><name sortKey="Na, Il Kang" sort="Na, Il Kang" uniqKey="Na I" first="Il-Kang" last="Na">Il-Kang Na</name>
<affiliation><nlm:aff id="JCI39395">Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="JCI39395">Department of Hematology and Oncology, Charité, Berlin, Germany.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Lu, Sydney X" sort="Lu, Sydney X" uniqKey="Lu S" first="Sydney X." last="Lu">Sydney X. Lu</name>
<affiliation><nlm:aff id="JCI39395">Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Yim, Nury L" sort="Yim, Nury L" uniqKey="Yim N" first="Nury L." last="Yim">Nury L. Yim</name>
<affiliation><nlm:aff id="JCI39395">Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Goldberg, Gabrielle L" sort="Goldberg, Gabrielle L" uniqKey="Goldberg G" first="Gabrielle L." last="Goldberg">Gabrielle L. Goldberg</name>
<affiliation><nlm:aff id="JCI39395">Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Tsai, Jennifer" sort="Tsai, Jennifer" uniqKey="Tsai J" first="Jennifer" last="Tsai">Jennifer Tsai</name>
<affiliation><nlm:aff id="JCI39395">Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Rao, Uttam" sort="Rao, Uttam" uniqKey="Rao U" first="Uttam" last="Rao">Uttam Rao</name>
<affiliation><nlm:aff id="JCI39395">Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Smith, Odette M" sort="Smith, Odette M" uniqKey="Smith O" first="Odette M." last="Smith">Odette M. Smith</name>
<affiliation><nlm:aff id="JCI39395">Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="King, Christopher G" sort="King, Christopher G" uniqKey="King C" first="Christopher G." last="King">Christopher G. King</name>
<affiliation><nlm:aff id="JCI39395">Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Suh, David" sort="Suh, David" uniqKey="Suh D" first="David" last="Suh">David Suh</name>
<affiliation><nlm:aff id="JCI39395">Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Hirschhorn Cymerman, Daniel" sort="Hirschhorn Cymerman, Daniel" uniqKey="Hirschhorn Cymerman D" first="Daniel" last="Hirschhorn-Cymerman">Daniel Hirschhorn-Cymerman</name>
<affiliation><nlm:aff id="JCI39395">Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Palomba, Lia" sort="Palomba, Lia" uniqKey="Palomba L" first="Lia" last="Palomba">Lia Palomba</name>
<affiliation><nlm:aff id="JCI39395">Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Penack, Olaf" sort="Penack, Olaf" uniqKey="Penack O" first="Olaf" last="Penack">Olaf Penack</name>
<affiliation><nlm:aff id="JCI39395">Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="JCI39395">Department of Hematology and Oncology, Charité, Berlin, Germany.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Holland, Amanda M" sort="Holland, Amanda M" uniqKey="Holland A" first="Amanda M." last="Holland">Amanda M. Holland</name>
<affiliation><nlm:aff id="JCI39395">Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="JCI39395">Department of Immunology, Weill Cornell Graduate School of Medical Sciences, New York, New York, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Jenq, Robert R" sort="Jenq, Robert R" uniqKey="Jenq R" first="Robert R." last="Jenq">Robert R. Jenq</name>
<affiliation><nlm:aff id="JCI39395">Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ghosh, Arnab" sort="Ghosh, Arnab" uniqKey="Ghosh A" first="Arnab" last="Ghosh">Arnab Ghosh</name>
<affiliation><nlm:aff id="JCI39395">Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Tran, Hien" sort="Tran, Hien" uniqKey="Tran H" first="Hien" last="Tran">Hien Tran</name>
<affiliation><nlm:aff id="JCI39395">Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Merghoub, Taha" sort="Merghoub, Taha" uniqKey="Merghoub T" first="Taha" last="Merghoub">Taha Merghoub</name>
<affiliation><nlm:aff id="JCI39395">Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Liu, Chen" sort="Liu, Chen" uniqKey="Liu C" first="Chen" last="Liu">Chen Liu</name>
<affiliation><nlm:aff id="JCI39395">Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sempowski, Gregory D" sort="Sempowski, Gregory D" uniqKey="Sempowski G" first="Gregory D." last="Sempowski">Gregory D. Sempowski</name>
<affiliation><nlm:aff id="JCI39395">Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ventevogel, Melissa" sort="Ventevogel, Melissa" uniqKey="Ventevogel M" first="Melissa" last="Ventevogel">Melissa Ventevogel</name>
<affiliation><nlm:aff id="JCI39395">Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Beauchemin, Nicole" sort="Beauchemin, Nicole" uniqKey="Beauchemin N" first="Nicole" last="Beauchemin">Nicole Beauchemin</name>
<affiliation><nlm:aff id="JCI39395">Goodman Cancer Centre, Department of Biochemistry, Department of Medicine, and Department of Oncology, McGill University, Montreal, Quebec, Canada.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Van Den Brink, Marcel R M" sort="Van Den Brink, Marcel R M" uniqKey="Van Den Brink M" first="Marcel R. M." last="Van Den Brink">Marcel R. M. Van Den Brink</name>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">19955659</idno>
<idno type="pmc">2798682</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2798682</idno>
<idno type="RBID">PMC:2798682</idno>
<idno type="doi">10.1172/JCI39395</idno>
<date when="2009">2009</date>
<idno type="wicri:Area/Pmc/Corpus">000703</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000703</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">The cytolytic molecules Fas ligand and TRAIL are required for murine thymic graft-versus-host disease</title>
<author><name sortKey="Na, Il Kang" sort="Na, Il Kang" uniqKey="Na I" first="Il-Kang" last="Na">Il-Kang Na</name>
<affiliation><nlm:aff id="JCI39395">Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="JCI39395">Department of Hematology and Oncology, Charité, Berlin, Germany.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Lu, Sydney X" sort="Lu, Sydney X" uniqKey="Lu S" first="Sydney X." last="Lu">Sydney X. Lu</name>
<affiliation><nlm:aff id="JCI39395">Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Yim, Nury L" sort="Yim, Nury L" uniqKey="Yim N" first="Nury L." last="Yim">Nury L. Yim</name>
<affiliation><nlm:aff id="JCI39395">Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Goldberg, Gabrielle L" sort="Goldberg, Gabrielle L" uniqKey="Goldberg G" first="Gabrielle L." last="Goldberg">Gabrielle L. Goldberg</name>
<affiliation><nlm:aff id="JCI39395">Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Tsai, Jennifer" sort="Tsai, Jennifer" uniqKey="Tsai J" first="Jennifer" last="Tsai">Jennifer Tsai</name>
<affiliation><nlm:aff id="JCI39395">Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Rao, Uttam" sort="Rao, Uttam" uniqKey="Rao U" first="Uttam" last="Rao">Uttam Rao</name>
<affiliation><nlm:aff id="JCI39395">Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Smith, Odette M" sort="Smith, Odette M" uniqKey="Smith O" first="Odette M." last="Smith">Odette M. Smith</name>
<affiliation><nlm:aff id="JCI39395">Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="King, Christopher G" sort="King, Christopher G" uniqKey="King C" first="Christopher G." last="King">Christopher G. King</name>
<affiliation><nlm:aff id="JCI39395">Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Suh, David" sort="Suh, David" uniqKey="Suh D" first="David" last="Suh">David Suh</name>
<affiliation><nlm:aff id="JCI39395">Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Hirschhorn Cymerman, Daniel" sort="Hirschhorn Cymerman, Daniel" uniqKey="Hirschhorn Cymerman D" first="Daniel" last="Hirschhorn-Cymerman">Daniel Hirschhorn-Cymerman</name>
<affiliation><nlm:aff id="JCI39395">Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Palomba, Lia" sort="Palomba, Lia" uniqKey="Palomba L" first="Lia" last="Palomba">Lia Palomba</name>
<affiliation><nlm:aff id="JCI39395">Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Penack, Olaf" sort="Penack, Olaf" uniqKey="Penack O" first="Olaf" last="Penack">Olaf Penack</name>
<affiliation><nlm:aff id="JCI39395">Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="JCI39395">Department of Hematology and Oncology, Charité, Berlin, Germany.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Holland, Amanda M" sort="Holland, Amanda M" uniqKey="Holland A" first="Amanda M." last="Holland">Amanda M. Holland</name>
<affiliation><nlm:aff id="JCI39395">Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="JCI39395">Department of Immunology, Weill Cornell Graduate School of Medical Sciences, New York, New York, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Jenq, Robert R" sort="Jenq, Robert R" uniqKey="Jenq R" first="Robert R." last="Jenq">Robert R. Jenq</name>
<affiliation><nlm:aff id="JCI39395">Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ghosh, Arnab" sort="Ghosh, Arnab" uniqKey="Ghosh A" first="Arnab" last="Ghosh">Arnab Ghosh</name>
<affiliation><nlm:aff id="JCI39395">Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Tran, Hien" sort="Tran, Hien" uniqKey="Tran H" first="Hien" last="Tran">Hien Tran</name>
<affiliation><nlm:aff id="JCI39395">Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Merghoub, Taha" sort="Merghoub, Taha" uniqKey="Merghoub T" first="Taha" last="Merghoub">Taha Merghoub</name>
<affiliation><nlm:aff id="JCI39395">Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Liu, Chen" sort="Liu, Chen" uniqKey="Liu C" first="Chen" last="Liu">Chen Liu</name>
<affiliation><nlm:aff id="JCI39395">Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sempowski, Gregory D" sort="Sempowski, Gregory D" uniqKey="Sempowski G" first="Gregory D." last="Sempowski">Gregory D. Sempowski</name>
<affiliation><nlm:aff id="JCI39395">Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ventevogel, Melissa" sort="Ventevogel, Melissa" uniqKey="Ventevogel M" first="Melissa" last="Ventevogel">Melissa Ventevogel</name>
<affiliation><nlm:aff id="JCI39395">Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Beauchemin, Nicole" sort="Beauchemin, Nicole" uniqKey="Beauchemin N" first="Nicole" last="Beauchemin">Nicole Beauchemin</name>
<affiliation><nlm:aff id="JCI39395">Goodman Cancer Centre, Department of Biochemistry, Department of Medicine, and Department of Oncology, McGill University, Montreal, Quebec, Canada.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Van Den Brink, Marcel R M" sort="Van Den Brink, Marcel R M" uniqKey="Van Den Brink M" first="Marcel R. M." last="Van Den Brink">Marcel R. M. Van Den Brink</name>
<affiliation><nlm:aff>NONE</nlm:aff>
</affiliation>
</author>
</analytic>
<series><title level="j">The Journal of Clinical Investigation</title>
<idno type="ISSN">0021-9738</idno>
<idno type="eISSN">1558-8238</idno>
<imprint><date when="2009">2009</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p>Thymic graft-versus-host disease (tGVHD) can contribute to profound T cell deficiency and repertoire restriction after allogeneic BM transplantation (allo-BMT). However, the cellular mechanisms of tGVHD and interactions between donor alloreactive T cells and thymic tissues remain poorly defined. Using clinically relevant murine allo-BMT models, we show here that even minimal numbers of donor alloreactive T cells, which caused mild nonlethal systemic graft-versus-host disease, were sufficient to damage the thymus, delay T lineage reconstitution, and compromise donor peripheral T cell function. Furthermore, to mediate tGVHD, donor alloreactive T cells required trafficking molecules, including CCR9, L selectin, P selectin glycoprotein ligand-1, the integrin subunits α<sub>E</sub>
and β<sub>7</sub>
, CCR2, and CXCR3, and costimulatory/inhibitory molecules, including Ox40 and carcinoembryonic antigen-associated cell adhesion molecule 1. We found that radiation in BMT conditioning regimens upregulated expression of the death receptors Fas and death receptor 5 (DR5) on thymic stromal cells (especially epithelium), while decreasing expression of the antiapoptotic regulator cellular caspase-8–like inhibitory protein. Donor alloreactive T cells used the cognate proteins FasL and TNF-related apoptosis-inducing ligand (TRAIL) (but not TNF or perforin) to mediate tGVHD, thereby damaging thymic stromal cells, cytoarchitecture, and function. Strategies that interfere with Fas/FasL and TRAIL/DR5 interactions may therefore represent a means to attenuate tGVHD and improve T cell reconstitution in allo-BMT recipients.
</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">J Clin Invest</journal-id>
<journal-id journal-id-type="publisher-id">J CLIN INVEST</journal-id>
<journal-title-group><journal-title>The Journal of Clinical Investigation</journal-title>
</journal-title-group>
<issn pub-type="ppub">0021-9738</issn>
<issn pub-type="epub">1558-8238</issn>
<publisher><publisher-name>American Society for Clinical Investigation</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">19955659</article-id>
<article-id pub-id-type="pmc">2798682</article-id>
<article-id pub-id-type="publisher-id">39395</article-id>
<article-id pub-id-type="doi">10.1172/JCI39395</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>The cytolytic molecules Fas ligand and TRAIL are required for murine thymic graft-versus-host disease</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Na</surname>
<given-names>Il-Kang</given-names>
</name>
<xref ref-type="aff" rid="JCI39395">1</xref>
<xref ref-type="aff" rid="JCI39395">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lu</surname>
<given-names>Sydney X.</given-names>
</name>
<xref ref-type="aff" rid="JCI39395">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Yim</surname>
<given-names>Nury L.</given-names>
</name>
<xref ref-type="aff" rid="JCI39395">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Goldberg</surname>
<given-names>Gabrielle L.</given-names>
</name>
<xref ref-type="aff" rid="JCI39395">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Tsai</surname>
<given-names>Jennifer</given-names>
</name>
<xref ref-type="aff" rid="JCI39395">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Rao</surname>
<given-names>Uttam</given-names>
</name>
<xref ref-type="aff" rid="JCI39395">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Smith</surname>
<given-names>Odette M.</given-names>
</name>
<xref ref-type="aff" rid="JCI39395">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>King</surname>
<given-names>Christopher G.</given-names>
</name>
<xref ref-type="aff" rid="JCI39395">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Suh</surname>
<given-names>David</given-names>
</name>
<xref ref-type="aff" rid="JCI39395">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hirschhorn-Cymerman</surname>
<given-names>Daniel</given-names>
</name>
<xref ref-type="aff" rid="JCI39395">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Palomba</surname>
<given-names>Lia</given-names>
</name>
<xref ref-type="aff" rid="JCI39395">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Penack</surname>
<given-names>Olaf</given-names>
</name>
<xref ref-type="aff" rid="JCI39395">1</xref>
<xref ref-type="aff" rid="JCI39395">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Holland</surname>
<given-names>Amanda M.</given-names>
</name>
<xref ref-type="aff" rid="JCI39395">1</xref>
<xref ref-type="aff" rid="JCI39395">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Jenq</surname>
<given-names>Robert R.</given-names>
</name>
<xref ref-type="aff" rid="JCI39395">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ghosh</surname>
<given-names>Arnab</given-names>
</name>
<xref ref-type="aff" rid="JCI39395">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Tran</surname>
<given-names>Hien</given-names>
</name>
<xref ref-type="aff" rid="JCI39395">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Merghoub</surname>
<given-names>Taha</given-names>
</name>
<xref ref-type="aff" rid="JCI39395">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Liu</surname>
<given-names>Chen</given-names>
</name>
<xref ref-type="aff" rid="JCI39395">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Sempowski</surname>
<given-names>Gregory D.</given-names>
</name>
<xref ref-type="aff" rid="JCI39395">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ventevogel</surname>
<given-names>Melissa</given-names>
</name>
<xref ref-type="aff" rid="JCI39395">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Beauchemin</surname>
<given-names>Nicole</given-names>
</name>
<xref ref-type="aff" rid="JCI39395">6</xref>
</contrib>
<contrib contrib-type="author"><name><surname>van den Brink</surname>
<given-names>Marcel R.M.</given-names>
</name>
<xref ref-type="aff" rid="JCI39395">1
</xref>
</contrib>
</contrib-group>
<aff id="JCI39395"><label>1</label>
Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.<label>2</label>
Department of Hematology and Oncology, Charité, Berlin, Germany.<label>3</label>
Department of Immunology, Weill Cornell Graduate School of Medical Sciences, New York, New York, USA.<label>4</label>
Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida, USA.<label>5</label>
Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.<label>6</label>
Goodman Cancer Centre, Department of Biochemistry, Department of Medicine, and Department of Oncology, McGill University, Montreal, Quebec, Canada.</aff>
<author-notes><corresp>Address correspondence to: Marcel R.M. van den Brink, Memorial Sloan-Kettering Cancer Center, ZRC-1404, Mailbox 111, 1275 York Avenue, New York, New York 10065, USA. Phone: (646) 888-2304; Fax: (917) 432-2375; E-mail:
<email>vandenbm@mskcc.org</email>
.
</corresp>
<fn><p><bold>Authorship note:</bold>
Il-Kang Na and Sydney X. Lu contributed equally to this work.
</p>
</fn>
</author-notes>
<pub-date pub-type="epub"><day>1</day>
<month>12</month>
<year>2009</year>
</pub-date>
<pub-date pub-type="ppub"><day>4</day>
<month>1</month>
<year>2010</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>1</day>
<month>12</month>
<year>2009</year>
</pub-date>
<pmc-comment> PMC Release delay is 0 months and 0 days and was based on the
. </pmc-comment>
<volume>120</volume>
<issue>1</issue>
<fpage>343</fpage>
<lpage>356</lpage>
<history><date date-type="received"><day>7</day>
<month>8</month>
<year>2009</year>
</date>
<date date-type="accepted"><day>7</day>
<month>10</month>
<year>2009</year>
</date>
</history>
<permissions><copyright-statement>Copyright © 2010, American Society for Clinical Investigation</copyright-statement>
</permissions>
<abstract><p>Thymic graft-versus-host disease (tGVHD) can contribute to profound T cell deficiency and repertoire restriction after allogeneic BM transplantation (allo-BMT). However, the cellular mechanisms of tGVHD and interactions between donor alloreactive T cells and thymic tissues remain poorly defined. Using clinically relevant murine allo-BMT models, we show here that even minimal numbers of donor alloreactive T cells, which caused mild nonlethal systemic graft-versus-host disease, were sufficient to damage the thymus, delay T lineage reconstitution, and compromise donor peripheral T cell function. Furthermore, to mediate tGVHD, donor alloreactive T cells required trafficking molecules, including CCR9, L selectin, P selectin glycoprotein ligand-1, the integrin subunits α<sub>E</sub>
and β<sub>7</sub>
, CCR2, and CXCR3, and costimulatory/inhibitory molecules, including Ox40 and carcinoembryonic antigen-associated cell adhesion molecule 1. We found that radiation in BMT conditioning regimens upregulated expression of the death receptors Fas and death receptor 5 (DR5) on thymic stromal cells (especially epithelium), while decreasing expression of the antiapoptotic regulator cellular caspase-8–like inhibitory protein. Donor alloreactive T cells used the cognate proteins FasL and TNF-related apoptosis-inducing ligand (TRAIL) (but not TNF or perforin) to mediate tGVHD, thereby damaging thymic stromal cells, cytoarchitecture, and function. Strategies that interfere with Fas/FasL and TRAIL/DR5 interactions may therefore represent a means to attenuate tGVHD and improve T cell reconstitution in allo-BMT recipients.
</p>
</abstract>
</article-meta>
</front>
</pmc>
</record>
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