DAP12 Deficiency in Liver Allografts Results in Enhanced Donor DC Migration, Augmented Effector T Cell Responses and Abrogation of Transplant Tolerance

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.

• Publication year

  2014

• Venue

  American Journal of Transplantation

• Publication date

  2014-08-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1111/ajt.12757PMID 24935196PMCID PMC4107008
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Tolerogenic dendritic cells

  2016cited by this paper
• Roles of dendritic cells in murine hepatic warm and liver transplantation‐induced cold ischemia/reperfusion injury

  2013cited by this paper
• Structure, expression pattern and biological activity of molecular complex TREM-2/DAP12.

  2013cited by this paper
• Galectin‐1 Prolongs Survival of Mouse Liver Allografts From Flt3L‐Pretreated Donors

  2013cited by this paper
• CD39 expression by hepatic myeloid dendritic cells attenuates inflammation in liver transplant ischemia‐reperfusion injury in mice

  2013cited by this paper
• Dendritic cells limit fibroinflammatory injury in nonalcoholic steatohepatitis in mice

  2013cited by this paper
• Adoptive Transfer of Allogeneic Liver Sinusoidal Endothelial Cells Specifically Inhibits T-Cell Responses to Cognate Stimuli

  2013influential reference
• Hepatocytes Contribute to Immune Regulation in the Liver by Activation of the Notch Signaling Pathway in T Cells

  2013cited by this paper
• Inhibition of Innate Co‐Receptor TREM‐1 Signaling Reduces CD4+ T Cell Activation and Prolongs Cardiac Allograft Survival

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• Dendritic cell regulation of carbon tetrachloride–induced murine liver fibrosis regression

  2012cited by this paper
• Suppression of histone deacetylase 11 promotes expression of IL-10 in Kupffer cells and induces tolerance following orthotopic liver transplantation in rats.

  2012influential reference
• Hepatic Stellate Cells Undermine the Allostimulatory Function of Liver Myeloid Dendritic Cells via STAT3-Dependent Induction of IDO

  2012cited by this paper
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  2012cited by this paper
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  2012cited by this paper
• IL-27 Production and STAT3-Dependent Upregulation of B7-H1 Mediate Immune Regulatory Functions of Liver Plasmacytoid Dendritic Cells

  2012cited by this paper
• DAP12 Promotes IRAK-M Expression and IL-10 Production by Liver Myeloid Dendritic Cells and Restrains Their T Cell Allostimulatory Ability

  2011cited by this paper
• Hepatic B7 homolog 1 expression is essential for controlling cold ischemia/reperfusion injury after mouse liver transplantation

  2011cited by this paper
• Liver antigen-presenting cells.

  2011cited by this paper
• Immunologic basis of graft rejection and tolerance following transplantation of liver or other solid organs.

  2011cited by this paper
• PD‐1/B7‐H1 Interaction Contribute to the Spontaneous Acceptance of Mouse Liver Allograft

  2010influential reference
• Conventional DCs reduce liver ischemia/reperfusion injury in mice via IL-10 secretion.

  2010cited by this paper
• Dynamic Regulation of CD8 T Cell Tolerance Induction by Liver Sinusoidal Endothelial Cells

  2010influential reference
• Antigen-presenting cell function in the tolerogenic liver environment

  2010cited by this paper
• The expanding roles of ITAM adapters FcRγ and DAP12 in myeloid cells

  2009cited by this paper
• NOD2 Ligation Subverts IFN-α Production by Liver Plasmacytoid Dendritic Cells and Inhibits Their T Cell Allostimulatory Activity via B7-H1 Up-Regulation1

  2009cited by this paper
• DAP10‐ and DAP12‐associated receptors in innate immunity

  2009cited by this paper
• Macrophage colony-stimulating factor induces the proliferation and survival of macrophages via a pathway involving DAP12 and β-catenin

  2009cited by this paper
• Human Liver Dendritic Cells Promote T Cell Hyporesponsiveness1

  2009influential reference
• Constitutive ablation of dendritic cells breaks self-tolerance of CD4 T cells and results in spontaneous fatal autoimmunity

  2009cited by this paper
• The liver as a lymphoid organ.

  2009cited by this paper
• Mechanism of T cell tolerance induction by murine hepatic Kupffer cells

  2008cited by this paper
• Plasmacytoid dendritic cells mediate oral tolerance.

  2008cited by this paper
• Role of Kupffer cells in the induction of tolerance of orthotopic liver transplantation in rats

  2008cited by this paper
• New Insights into Mechanisms of Spontaneous Liver Transplant Tolerance: The Role of Foxp3‐Expressing CD25+CD4+ Regulatory T Cells

  2008cited by this paper
• Increased diabetes development and decreased function of CD4+CD25+ Treg in the absence of a functional DAP12 adaptor protein

  2008cited by this paper
• Hepatic microenvironment programs hematopoietic progenitor differentiation into regulatory dendritic cells, maintaining liver tolerance.

  2008cited by this paper
• Increased TLR responses in dendritic cells lacking the ITAM‐containing adapters DAP12 and FcRγ

  2008cited by this paper
• The TREM-1/DAP12 pathway.

  2008cited by this paper
• The many faces of ITAMs.

  2007cited by this paper
• Blockade of TREM‐2 exacerbates experimental autoimmune encephalomyelitis

  2007cited by this paper
• Tolerogenic maturation of liver sinusoidal endothelial cells promotes B7‐homolog 1‐dependent CD8+ T cell tolerance

  2007cited by this paper
• The liver: a special case in transplantation tolerance.

  2007cited by this paper
• Tolerogenic dendritic cells and the quest for transplant tolerance

  2007cited by this paper
• Gut‐derived commensal bacterial products inhibit liver dendritic cell maturation by stimulating hepatic interleukin‐6/signal transducer and activator of transcription 3 activity

  2007cited by this paper
• Dendritic cells, the liver, and transplantation

  2007cited by this paper
• Rapamycin-Conditioned Dendritic Cells Are Poor Stimulators of Allogeneic CD4+ T Cells, but Enrich for Antigen-Specific Foxp3+ T Regulatory Cells and Promote Organ Transplant Tolerance1

  2007cited by this paper
• Activating and inhibitory functions of DAP12

  2007cited by this paper
• Critical Negative Regulation of Type 1 T Cell Immunity and Immunopathology by Signaling Adaptor DAP12 during Intracellular Infection1

  2007influential reference
• DAP12 signaling regulates plasmacytoid dendritic cell homeostasis and down-modulates their function during viral infection.

  2006cited by this paper
• Siglec-H is an IPC-specific receptor that modulates type I IFN secretion through DAP12.

  2006cited by this paper
• Liver Sinusoidal Endothelial Cells That Endocytose Allogeneic Cells Suppress T Cells with Indirect Allospecificity1

  2006cited by this paper
• DAP12 Signaling Regulates Plasmacytoid Dendritic Cell Homeostasis and Down-Modulates Their Function during Viral Infection1

  2006cited by this paper
• An Appraisal of Tolerance in Liver Transplantation

  2006cited by this paper
• Cellular and molecular mechanisms of liver tolerance

  2006cited by this paper
• Enhanced Toll-like receptor responses in the absence of signaling adaptor DAP12

  2005cited by this paper
• CTLA4 Engagement is Required for Induction of Murine Liver Transplant Spontaneous Tolerance †

  2005cited by this paper
• KARAP/DAP12/TYROBP: three names and a multiplicity of biological functions

  2005cited by this paper
• Cross‐presentation of oral antigens by liver sinusoidal endothelial cells leads to CD8 T cell tolerance

  2005cited by this paper
• Low TLR4 Expression by Liver Dendritic Cells Correlates with Reduced Capacity to Activate Allogeneic T Cells in Response to Endotoxin1

  2005cited by this paper
• Liver Dendritic Cells Are Less Immunogenic Than Spleen Dendritic Cells because of Differences in Subtype Composition1

  2004cited by this paper
• Tolerogenic dendritic cells.

  2003cited by this paper
• Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice.

  2003cited by this paper
• IL-12 Antagonism Enhances Apoptotic Death of T Cells Within Hepatic Allografts from Flt3 Ligand-Treated Donors and Promotes Graft Acceptance1

  2001cited by this paper
• Quantitative reverse transcription-polymerase chain reaction to study mRNA decay: comparison of endpoint and real-time methods.

  2000cited by this paper
• The Role of the DAP12 Signal in Mouse Myeloid Differentiation1

  2000cited by this paper
• Effects of Liver-Derived Dendritic Cell Progenitors on Th1- and Th2-Like Cytokine Responses In Vitro and In Vivo1

  2000cited by this paper
• Differences Among HIV-1 Variants in Their Ability to Elicit Secretion of TNF-α1

  2000cited by this paper
• Molecular cloning, gene structure, and expression pattern of pig immunoreceptor DAP12

  2000cited by this paper
• Are dendritic cells the key to liver transplant tolerance?

  1999cited by this paper
• Donor pretreatment with Flt-3 ligand augments antidonor cytotoxic T lymphocyte, natural killer, and lymphokine-activated killer cell activities within liver allografts and alters the pattern of intragraft apoptotic activity.

  1998cited by this paper
• Immunoreceptor DAP12 bearing a tyrosine-based activation motif is involved in activating NK cells

  1998cited by this paper
• Apoptosis within spontaneously accepted mouse liver allografts: evidence for deletion of cytotoxic T cells and implications for tolerance induction.

  1997cited by this paper
• Banff schema for grading liver allograft rejection: An international consensus document

  1997cited by this paper
• Liver transplants contribute to their own success

  1996cited by this paper
• Granulocyte/macrophage colony-stimulating factor-stimulated hepatic dendritic cell progenitors prolong pancreatic islet allograft survival.

  1995cited by this paper
• In vitro propagation and homing of liver-derived dendritic cell progenitors to lymphoid tissues of allogeneic recipients. Implications for the establishment and maintenance of donor cell chimerism following liver transplantation.

  1995cited by this paper
• Growth of donor-derived dendritic cells from the bone marrow of murine liver allograft recipients in response to granulocyte/macrophage colony- stimulating factor

  1995cited by this paper
• DELETION OF SPONTANEOUS RAT LIVER ALLOGRAFT ACCEPTANCE BY DONOR IRRADIATION

  1995cited by this paper
• FcR gamma chain deletion results in pleiotrophic effector cell defects.

  1994cited by this paper
• Murine liver allograft transplantation: Tolerance and donor cell chimerism

  1994cited by this paper
• FcR γ chain deletion results in pleiotrophic effector cell defects

  1994cited by this paper
• Propagation of dendritic cell progenitors from normal mouse liver using granulocyte/macrophage colony-stimulating factor and their maturational development in the presence of type-1 collagen

  1994cited by this paper
• The immunology of experimental liver transplantation in the rat.

  1985cited by this paper
• Induction of Immunological Tolerance by Porcine Liver Allografts

  1969cited by this paper

• Clinical and Experimental Immune Tolerance in Pediatric Liver Transplantation

  2026cites this paper
• Mouse orthotopic liver transplantation: challenges, achievements and applications.

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  2024cites this paper
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  2024cites this paper
• Bile Duct Stent and Strain Selection Influences Long-Term Survival of Mouse Orthotopic Liver Transplantation.

  2023cites this paper
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  2021cites this paper
• Details determining the success in establishing a mouse orthotopic liver transplantation model

  2020cites this paper
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  2020cites this paper
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  2020cites this paper
• Strategies for Deliberate Induction of Immune Tolerance in Liver Transplantation: From Preclinical Models to Clinical Application

  2020cites this paper
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  2020cites this paper
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  2020cites this paper
• Antigen presentation, autoantibody production, and therapeutic targets in autoimmune liver disease

  2020cites this paper
• Donor plasmacytoid dendritic cells modulate effector and regulatory T cell responses in mouse spontaneous liver transplant tolerance

  2020cites this paper
• DNAX Activating Protein of 12 kDa/Triggering Receptor Expressed on Myeloid Cells 2 Expression by Mouse and Human Liver Dendritic Cells: Functional Implications and Regulation of Liver Ischemia–Reperfusion Injury

  2019cites this paper
• Graft‐infiltrating PD‐L1hi cross‐dressed dendritic cells regulate antidonor T cell responses in mouse liver transplant tolerance

  2018cites this paper
• Hepatic Dendritic Cells, the Tolerogenic Liver Environment, and Liver Disease

  2018cites this paper
• Regulatory dendritic cells: profiling, targeting, and therapeutic application

  2018cites this paper
• Maintaining T cell tolerance of alloantigens: Lessons from animal studies

  2018cites this paper
• Orthotopic mouse liver transplantation to study liver biology and allograft tolerance

  2016cites this paper
• Liver transplantation in the mouse: Insights into liver immunobiology, tissue injury, and allograft tolerance

  2016cites this paper
• Stellate Cells in Hepatic Immunological Tolerance

  2015cites this paper
• CD39 deficiency in murine liver allografts promotes inflammatory injury and immune-mediated rejection

  2015influential citation
• World Journal of Gastroenterology

  year unknowncites this paper