A DAP12-mediated pathway regulates expression of CC chemokine receptor 7 and maturation of human dendritic cells.
Gene targeting of the adaptor molecule DAP12 in mice caused abnormal distribution and impaired antigen presentation capacity of dendritic cells (DCs). However, the DAP12-associated receptors expressed on DCs and their functions have not been identified yet. Here we show that the triggering receptor expressed on myeloid cells-2 (TREM-2) is a cell surface receptor on human monocyte-derived DCs, which is associated with DAP12. TREM-2/DAP12 promotes upregulation of CC chemokine receptor 7, partial DC maturation, and DC survival through activation of protein tyrosine kinases and extracellular signal-regulated kinase. In contrast to Toll-like receptor-mediated signaling, TREM2/DAP12 stimulation is independent of nuclear factor-kappaB and p38 stress-activated protein kinase. This novel DC activation pathway may regulate DC homeostasis and amplify DC responses to pathogens, explaining the phenotype observed in DAP12-deficient mice.
Bouchon
A
A
Basel Institute for Immunology, CH-4005 Basel, Switzerland.
Hernández-Munain
C
C
Cella
M
M
Colonna
M
M
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D051940:B7-2 Antigen; D019013:CD40 Antigens / Q000096:biosynthesis; D002454:Cell Differentiation; D002460:Cell Line; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D006801:Humans; D020672:I-kappa B Proteins; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000096:biosynthesis* / Q000235:genetics; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases
D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D051940:B7-2 Antigen; C515370:CCR7 protein, human; D019013:CD40 Antigens; C497964:CD86 protein, human; C515371:Ccr7 protein, mouse; C497965:Cd86 protein, mouse; D004268:DNA-Binding Proteins; D000949:Histocompatibility Antigens Class II; D020672:I-kappa B Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D011971:Receptors, Immunologic; C408842:TREM1 protein, human; C498715:TREM2 protein, human; C110546:TYROBP protein, human; C498716:Trem2 protein, mouse; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D000072000:NF-KappaB Inhibitor alpha; D011505:Protein-Tyrosine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases