DAP12 Deficiency in Liver Allografts Results in Enhanced Donor DC Migration, Augmented Effector T Cell Responses and Abrogation of Transplant Tolerance
Identifieur interne : 005678 ( Main/Exploration ); précédent : 005677; suivant : 005679DAP12 Deficiency in Liver Allografts Results in Enhanced Donor DC Migration, Augmented Effector T Cell Responses and Abrogation of Transplant Tolerance
Auteurs : O. Yoshida [États-Unis] ; S. Kimura [États-Unis] ; L. Dou [États-Unis, République populaire de Chine] ; B. M. Matta [États-Unis] ; S. Yokota [États-Unis] ; M. A. Ross [États-Unis] ; D. A. Geller [États-Unis] ; A. W. Thomson [États-Unis, Panama]Source :
- American journal of transplantation : (Print) [ 1600-6135 ] ; 2014.
Descripteurs français
- KwdFr :
- Animaux, Cellules dendritiques (cytologie), Foie (métabolisme), Inflammation, Leucocytes (cytologie), Lymphocytes T (cytologie), Lymphocytes T CD4+ (cytologie), Mouvement cellulaire, Mâle, Phénotype, Protéines adaptatrices de la transduction du signal (génétique), Protéines adaptatrices de la transduction du signal (métabolisme), Rate (métabolisme), Souris, Souris de lignée C57BL, Souris transgéniques, Transplantation cellulaire, Transplantation hépatique.
- MESH :
- cytologie : Cellules dendritiques, Leucocytes, Lymphocytes T, Lymphocytes T CD4+.
- génétique : Protéines adaptatrices de la transduction du signal.
- métabolisme : Foie, Protéines adaptatrices de la transduction du signal, Rate.
- Pascal (Inist)
- Animaux, Déficit, Foie, Inflammation, Mouvement cellulaire, Mâle, Phénotype, Résultat, Homotransplantation, Donneur limite, Homme, Migration cellulaire, Cellule effectrice, Réponse immune, Immunité cellulaire, Souris, Souris de lignée C57BL, Souris transgéniques, Tolérance immune, Transplantation, Cellule dendritique, Cellule APC, Cellule accessoire, Lymphocyte T, Traitement, Gène DAP12, Transplantation cellulaire, Transplantation hépatique.
- Wicri :
English descriptors
- KwdEn :
- Accessory cell, Adaptor Proteins, Signal Transducing (genetics), Adaptor Proteins, Signal Transducing (metabolism), Animals, Antigen presenting cell, CD4-Positive T-Lymphocytes (cytology), Cell Movement, Cell Transplantation, Cell migration, Cellular immunity, Deficiency, Dendritic Cells (cytology), Dendritic cell, Effectory cell, Homotransplantation, Human, Immune response, Immune tolerance, Inflammation, Leukocytes (cytology), Liver, Liver (metabolism), Liver Transplantation, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Phenotype, Result, Spleen (metabolism), Suboptimal donor, T-Lymphocyte, T-Lymphocytes (cytology), Transplantation, Treatment.
- MESH :
- chemical , genetics : Adaptor Proteins, Signal Transducing.
- chemical , metabolism : Adaptor Proteins, Signal Transducing.
- cytology : CD4-Positive T-Lymphocytes, Dendritic Cells, Leukocytes, T-Lymphocytes.
- metabolism : Liver, Spleen.
- Animals, Cell Movement, Cell Transplantation, Inflammation, Liver Transplantation, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Phenotype.
Abstract
Liver interstitial dendritic cells (DC) have been implicated in immune regulation and tolerance induction. We found that the transmembrane immuno-adaptor DNAX-activating protein of 12 kDa (DAP12) negatively regulated conventional liver myeloid (m) DC maturation and their in vivo migratory and T cell allostimulatory ability. Livers were transplanted from C57BL/6(H2b) (B6) WT or DAP12-/- mice into WT C3H (H2k) recipients. Donor mDC (H2-Kb+CD11c+) were quantified in spleens by flow cytometry. Anti-donor T cell reactivity was evaluated by ex vivo carboxyfluorescein diacetate succinimidyl ester-mixed leukocyte reaction and delayed-type hypersensitivity responses, while T effector and regulatory T cells were determined by flow analysis. A threefold to fourfold increase in donor-derived DC was detected in spleens of DAP12-/- liver recipients compared with those given WT grafts. Moreover, pro-inflammatory cytokine gene expression in the graft, interferon gamma (IFNγ) production by graft-infiltrating CD8+ T cells and systemic levels of IFNγ were all elevated significantly in DAP12-/- liver recipients. DAP12-/- grafts also exhibited reduced incidences of CD4+Foxp3+ cells and enhanced CD8+ T cell IFNγ secretion in response to donor antigen challenge. Unlike WT grafts, DAP12-/- livers failed to induce tolerance and were rejected acutely. Thus, DAP12 expression in liver grafts regulates donor mDC migration to host lymphoid tissue, alloreactive T cell responses and transplant tolerance.
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Matta</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine</s1><s2>Pittsburgh, PA</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Pittsburgh, PA</wicri:noRegion></affiliation></author><author><name sortKey="Yokota, S" sort="Yokota, S" uniqKey="Yokota S" first="S." last="Yokota">S. Yokota</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine</s1><s2>Pittsburgh, PA</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Pittsburgh, PA</wicri:noRegion></affiliation></author><author><name sortKey="Ross, M A" sort="Ross, M A" uniqKey="Ross M" first="M. A." last="Ross">M. A. Ross</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Center for Biologic Imaging, University of Pittsburgh School of Medicine</s1><s2>Pittsburgh, PA</s2><s3>USA</s3><sZ>6 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Pittsburgh, PA</wicri:noRegion></affiliation></author><author><name sortKey="Geller, D A" sort="Geller, D A" uniqKey="Geller D" first="D. A." last="Geller">D. A. 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Yoshida</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine</s1><s2>Pittsburgh, PA</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Pittsburgh, PA</wicri:noRegion></affiliation></author><author><name sortKey="Kimura, S" sort="Kimura, S" uniqKey="Kimura S" first="S." last="Kimura">S. Kimura</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine</s1><s2>Pittsburgh, PA</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Pittsburgh, PA</wicri:noRegion></affiliation></author><author><name sortKey="Dou, L" sort="Dou, L" uniqKey="Dou L" first="L." last="Dou">L. Dou</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine</s1><s2>Pittsburgh, PA</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Pittsburgh, PA</wicri:noRegion></affiliation><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Hepatic Surgery Center, Tongji Hospital, Huazhong University of Science and Technology</s1><s2>Wuhan</s2><s3>CHN</s3><sZ>3 aut.</sZ></inist:fA14><country>République populaire de Chine</country><wicri:noRegion>Wuhan</wicri:noRegion></affiliation></author><author><name sortKey="Matta, B M" sort="Matta, B M" uniqKey="Matta B" first="B. M." last="Matta">B. M. Matta</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine</s1><s2>Pittsburgh, PA</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Pittsburgh, PA</wicri:noRegion></affiliation></author><author><name sortKey="Yokota, S" sort="Yokota, S" uniqKey="Yokota S" first="S." last="Yokota">S. Yokota</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine</s1><s2>Pittsburgh, PA</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Pittsburgh, PA</wicri:noRegion></affiliation></author><author><name sortKey="Ross, M A" sort="Ross, M A" uniqKey="Ross M" first="M. A." last="Ross">M. A. Ross</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Center for Biologic Imaging, University of Pittsburgh School of Medicine</s1><s2>Pittsburgh, PA</s2><s3>USA</s3><sZ>6 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Pittsburgh, PA</wicri:noRegion></affiliation></author><author><name sortKey="Geller, D A" sort="Geller, D A" uniqKey="Geller D" first="D. A." last="Geller">D. A. Geller</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine</s1><s2>Pittsburgh, PA</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Pittsburgh, PA</wicri:noRegion></affiliation></author><author><name sortKey="Thomson, A W" sort="Thomson, A W" uniqKey="Thomson A" first="A. W." last="Thomson">A. W. Thomson</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine</s1><s2>Pittsburgh, PA</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Pittsburgh, PA</wicri:noRegion></affiliation><affiliation wicri:level="3"><inist:fA14 i1="04"><s1>Department of Immunology, University of Pittsburgh School of Medicine</s1><s2>Pittsburgh</s2><s3>PAN</s3><sZ>8 aut.</sZ></inist:fA14><country>Panama</country><placeName><settlement type="city">Pittsburgh</settlement><region type="state">Pennsylvanie</region></placeName></affiliation></author></analytic><series><title level="j" type="main">American journal of transplantation : (Print)</title><title level="j" type="abbreviated">Am. j. transplant. : (Print)</title><idno type="ISSN">1600-6135</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">American journal of transplantation : (Print)</title><title level="j" type="abbreviated">Am. j. transplant. : (Print)</title><idno type="ISSN">1600-6135</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Accessory cell</term><term>Adaptor Proteins, Signal Transducing (genetics)</term><term>Adaptor Proteins, Signal Transducing (metabolism)</term><term>Animals</term><term>Antigen presenting cell</term><term>CD4-Positive T-Lymphocytes (cytology)</term><term>Cell Movement</term><term>Cell Transplantation</term><term>Cell migration</term><term>Cellular immunity</term><term>Deficiency</term><term>Dendritic Cells (cytology)</term><term>Dendritic cell</term><term>Effectory cell</term><term>Homotransplantation</term><term>Human</term><term>Immune response</term><term>Immune tolerance</term><term>Inflammation</term><term>Leukocytes (cytology)</term><term>Liver</term><term>Liver (metabolism)</term><term>Liver Transplantation</term><term>Male</term><term>Mice</term><term>Mice, Inbred C57BL</term><term>Mice, Transgenic</term><term>Phenotype</term><term>Result</term><term>Spleen (metabolism)</term><term>Suboptimal donor</term><term>T-Lymphocyte</term><term>T-Lymphocytes (cytology)</term><term>Transplantation</term><term>Treatment</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Cellules dendritiques (cytologie)</term><term>Foie (métabolisme)</term><term>Inflammation</term><term>Leucocytes (cytologie)</term><term>Lymphocytes T (cytologie)</term><term>Lymphocytes T CD4+ (cytologie)</term><term>Mouvement cellulaire</term><term>Mâle</term><term>Phénotype</term><term>Protéines adaptatrices de la transduction du signal (génétique)</term><term>Protéines adaptatrices de la transduction du signal (métabolisme)</term><term>Rate (métabolisme)</term><term>Souris</term><term>Souris de lignée C57BL</term><term>Souris transgéniques</term><term>Transplantation cellulaire</term><term>Transplantation hépatique</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Adaptor Proteins, Signal Transducing</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Adaptor Proteins, Signal Transducing</term></keywords><keywords scheme="MESH" qualifier="cytologie" xml:lang="fr"><term>Cellules dendritiques</term><term>Leucocytes</term><term>Lymphocytes T</term><term>Lymphocytes T CD4+</term></keywords><keywords scheme="MESH" qualifier="cytology" xml:lang="en"><term>CD4-Positive T-Lymphocytes</term><term>Dendritic Cells</term><term>Leukocytes</term><term>T-Lymphocytes</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Protéines adaptatrices de la transduction du signal</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Liver</term><term>Spleen</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Foie</term><term>Protéines adaptatrices de la transduction du signal</term><term>Rate</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Cell Movement</term><term>Cell Transplantation</term><term>Inflammation</term><term>Liver Transplantation</term><term>Male</term><term>Mice</term><term>Mice, Inbred C57BL</term><term>Mice, Transgenic</term><term>Phenotype</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Animaux</term><term>Déficit</term><term>Foie</term><term>Inflammation</term><term>Mouvement cellulaire</term><term>Mâle</term><term>Phénotype</term><term>Résultat</term><term>Homotransplantation</term><term>Donneur limite</term><term>Homme</term><term>Migration cellulaire</term><term>Cellule effectrice</term><term>Réponse immune</term><term>Immunité cellulaire</term><term>Souris</term><term>Souris de lignée C57BL</term><term>Souris transgéniques</term><term>Tolérance immune</term><term>Transplantation</term><term>Cellule dendritique</term><term>Cellule APC</term><term>Cellule accessoire</term><term>Lymphocyte T</term><term>Traitement</term><term>Gène DAP12</term><term>Transplantation cellulaire</term><term>Transplantation hépatique</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Déficit</term><term>Homme</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Liver interstitial dendritic cells (DC) have been implicated in immune regulation and tolerance induction. We found that the transmembrane immuno-adaptor DNAX-activating protein of 12 kDa (DAP12) negatively regulated conventional liver myeloid (m) DC maturation and their in vivo migratory and T cell allostimulatory ability. Livers were transplanted from C57BL/6(H2<sup>b</sup>) (B6) WT or DAP12<sup>-/-</sup> mice into WT C3H (H2<sup>k</sup>) recipients. Donor mDC (H2-K<sup>b+</sup>CD11c<sup>+</sup>) were quantified in spleens by flow cytometry. Anti-donor T cell reactivity was evaluated by ex vivo carboxyfluorescein diacetate succinimidyl ester-mixed leukocyte reaction and delayed-type hypersensitivity responses, while T effector and regulatory T cells were determined by flow analysis. A threefold to fourfold increase in donor-derived DC was detected in spleens of DAP12<sup>-/-</sup> liver recipients compared with those given WT grafts. Moreover, pro-inflammatory cytokine gene expression in the graft, interferon gamma (IFNγ) production by graft-infiltrating CD8<sup>+</sup> T cells and systemic levels of IFNγ were all elevated significantly in DAP12<sup>-/- </sup>liver recipients. DAP12<sup>-/-</sup> grafts also exhibited reduced incidences of CD4<sup>+</sup>Foxp3<sup>+</sup> cells and enhanced CD8<sup>+</sup> T cell IFNγ secretion in response to donor antigen challenge. Unlike WT grafts, DAP12<sup>-/-</sup> livers failed to induce tolerance and were rejected acutely. Thus, DAP12 expression in liver grafts regulates donor mDC migration to host lymphoid tissue, alloreactive T cell responses and transplant tolerance.</div></front></TEI><affiliations><list><country><li>Panama</li><li>République populaire de Chine</li><li>États-Unis</li></country><region><li>Pennsylvanie</li></region><settlement><li>Pittsburgh</li></settlement></list><tree><country name="États-Unis"><noRegion><name sortKey="Yoshida, O" sort="Yoshida, O" uniqKey="Yoshida O" first="O." last="Yoshida">O. Yoshida</name></noRegion><name sortKey="Dou, L" sort="Dou, L" uniqKey="Dou L" first="L." last="Dou">L. Dou</name><name sortKey="Geller, D A" sort="Geller, D A" uniqKey="Geller D" first="D. A." last="Geller">D. A. Geller</name><name sortKey="Kimura, S" sort="Kimura, S" uniqKey="Kimura S" first="S." last="Kimura">S. Kimura</name><name sortKey="Matta, B M" sort="Matta, B M" uniqKey="Matta B" first="B. M." last="Matta">B. M. Matta</name><name sortKey="Ross, M A" sort="Ross, M A" uniqKey="Ross M" first="M. A." last="Ross">M. A. Ross</name><name sortKey="Thomson, A W" sort="Thomson, A W" uniqKey="Thomson A" first="A. W." last="Thomson">A. W. Thomson</name><name sortKey="Yokota, S" sort="Yokota, S" uniqKey="Yokota S" first="S." last="Yokota">S. Yokota</name></country><country name="République populaire de Chine"><noRegion><name sortKey="Dou, L" sort="Dou, L" uniqKey="Dou L" first="L." last="Dou">L. Dou</name></noRegion></country><country name="Panama"><region name="Pennsylvanie"><name sortKey="Thomson, A W" sort="Thomson, A W" uniqKey="Thomson A" first="A. W." last="Thomson">A. W. Thomson</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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