02本文01_改正恒康.indd

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ゆあみねむら
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1 Cytometry Research Tsuneyasu Kaisho, M.D., Ph.D. Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University Abstract Dendritic cells (DCs) are professional antigen presenting cells involved not only in provoking innate immune responses but also in establishing adaptive immune responses. In order to clarify the critical in vivo roles of DCs, generation of gene-manipulated mice for DC ablation is very useful. DCs are heterogeneous and consist of various subsets, including plasmacytoid DCs (pdcs) or conventional DCs (cdcs). These DC subsets show the subset-specifi c functions. We have recently generated the mutant mice in which CD103 + CD11b - cdcs can be selectively ablated. The system is based on the selective expression of a chemokine receptor, XCR1, in the DC subset. CD103 + CD11b - cdcs are known for their high ability to incorporate dying cells and crosspresent the antigens to generate cytotoxic T cells. These functions are critical for protective responses against viral infection or tumors, but additional roles of the DC subset are largely unknown. By using our mutant mice, critical in vivo roles of the DC subset have been clarifi ed. Our mutant mice are superior to the mutant mice generated so far in terms of the selectivity of the cell ablation and marking. Therefore, the mice should contribute to the clarifi cation of additional roles of the DC subset. The DC subset is present also in the human. So the knowledge based on the mutant mice can be applicable to the human system. Key words : Dendritic cells; subset; chemokine receptor; crosspresentation dendritic cells DC DC 1973 Ralph M. Steinman Zanvil A. Cohn 1 B T 2011 Ralph M. Steinman DC DC DC 1

2 Dendritic cell subset functions diphteria toxin receptor DTR DTR DT DT DTR DTR DT DTR DTA DT DC CD11c DTR CD11c-DTR DC 2 CD11c-DTA T 2 DC 2 3 CD11c DC 10% CD11c 4 DTR DT CD11c-DTR CD11c-DTR Garbi bacterial artificial chromosome BAC CD11c-DOG 5 CD11c-DTR CD11c-DOG DC 6 CD11c DC DC DC DC pdc cdc cdc CD103 CD11b CD103 CD11b cdc CD103 CD11b cdc CD8 T CD103 CD11b cdc CD103 CD11b cdc T 7 T DC CD103 CD11b cdc MHC I CD103 CD11b cdc 8 CD103 CD11b cdc RNA TLR3 lipopolysaccharide LPS TLR4 CpG DNA TLR9 TLR TLR3 DC CD103 CD11b cdc TLR4 TLR9 DC CD103 CD11b cdc CD103 CD11b cdc 2

Cytometry Research 25 1 1 6 2015 CD103 CD11b cdc IRF-8 CD103 CD11b cdc PDC 9 IRF-8 BXH2 CD103 CD11b cdc 10 BATF-3 basic leucine zipper transcription factor, ATF-like 3cDC CD103 CD11b cdc 11 CD103

3 Cytometry Research CD103 CD11b cdc IRF-8 CD103 CD11b cdc PDC 9 IRF-8 BXH2 CD103 CD11b cdc 10 BATF-3 basic leucine zipper transcription factor, ATF-like 3cDC CD103 CD11b cdc 11 CD103 CD11b cdc IRF-8 B BATF-3 CD103 CD11b cdc CD103 CD11b cdc 1 CD103 CD11b cdc DC DC XCR venus DTR venus XCR1-venus XCR1-DTRvenus 14 CD103 CD11b cdc venus XCR1-DTRvenus CD103 CD11b cdc 2 3 CD103 CD11b cdc CD8 T 14 4CD103 CD11b cdc CD103 CD11b cdc Ruedl CD103 CD11b cdc DC NK lectin group receptor-1 CLEC9A CLEC9A BAC DTR CLEC9A-DTR 15 CLEC9A-DTR CD103 CD11b cdc CLEC9A PDC 1 1 CD205 DTR CD205-DTR 16 3

4 Dendritic cell subset functions CD205-DTR CD103 CD11b- cdc CD205 CD103 CD11b cdc 1 1 DTR DT 10 CD11c-DTR CD205-DTR XCR1-DTRvenus CLEC9A-DTR CD205-DTR XCR1-DTRvenus venus 1 N CC CXC CX3C XC XC N 1 XCL1XCL1 XCL2 XCL1 XCL2 98% 114 4

5 Cytometry Research XCR1 XC XCL1 NK CD8 T XCL1 CD8 T T DC pdc mdc mdc BDCA3 BDCA3 DC BDCA3 DC DC 10% BDCA3 DC TLR3 XCR BDCA3 DC 19 BDCA3 DC CD103 CD11b cdc XCR1 XCL1 NK CD8+ T XCL1 XCR1 CD103 CD11b cdc BDCA3 DC XCL1 XCR1 BDCA3 DC CD103+CD11b cdc Unanue CD103 CD11b cdc BATF3 20 CD103 CD11b cdc CD103 CD11b cdc CD103 CD11b cdc 1 Steinman RM, Cohn ZA. Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution. J Exp Med 137: , Bar-On L, Jung S. Defining dendritic cells by conditional and constitutive cell ablation. Immunol Rev 234:76-89, Ohnmacht C, Pullner A, King SB et al. Constitutive ablation of dendritic cells breaks self-tolerance of CD4 T cells and results in spontaneous fatal autoimmunity. J Exp Med 206:549-59, Sathaliyawala T, O'Gorman WE, Greter M et al. Mammalian target of rapamycin controls dendritic cell development downstream of Flt3 ligand signaling. Immunity 33: , Hochweller K, Striegler J, Hammerling GJ, Garbi N. A novel CD11c.DTR transgenic mouse for depletion of dendritic cells reveals their requirement for homeostatic proliferation of natural killer cells. Eur J Immunol 38: , Tittel AP, Heuser C, Ohliger C et al. Functionally relevant neutrophilia in CD11c diphtheria toxin receptor transgenic mice. Nat Methods 9:385-90, Shortman K, Heath WR. The CD8+ dendritic cell subset. Immunol Rev 234:18-31, Dudziak D, Kamphorst AO, Heidkamp GF et al. Differential antigen processing by dendritic cell subsets in vivo. Science 315:107-11, Tsujimura H, Tamura T, Ozato K. Cutting edge: IFN consensus sequence binding protein/ifn regulatory factor 8 drives the development of type I IFNproducing plasmacytoid dendritic cells. J Immunol 170:1131-5, Tailor P, Tamura T, Morse HC, 3rd, Ozato K. The BXH2 mutation in IRF8 differentially impairs dendritic cell subset development in the mouse. Blood 111:1942-5,

6 Dendritic cell subset functions 11 Hildner K, Edelson BT, Purtha WE et al. Batf3 deficiency reveals a critical role for CD8alpha+ dendritic cells in cytotoxic T cell immunity. Science 322: , Dorner BG, Dorner MB, Zhou X et al. Selective expression of the chemokine receptor XCR1 on crosspresenting dendritic cells determines cooperation with CD8+ T cells. Immunity 31:823-33, Yamazaki C, Miyamoto R, Hoshino K et al. Conservation of a chemokine system, XCR1 and its ligand, XCL1, between human and mice. Biochem Biophys Res Commun 397:756-61, Yamazaki C, Sugiyama M, Ohta T et al. Critical roles of a dendritic cell subset expressing a chemokine receptor, XCR1. J Immunol 190: , Piva L, Tetlak P, Claser C, Karjalainen K, Renia L, Ruedl C. Cutting edge: Clec9A+ dendritic cells mediate the development of experimental cerebral malaria. J Immunol 189: , Fukaya T, Murakami R, Takagi H et al. Conditional ablation of CD205+ conventional dendritic cells impacts the regulation of T-cell immunity and homeostasis in vivo. Proc Natl Acad Sci U S A 109: , Lei Y, Ripen AM, Ishimaru N et al. Aire-dependent production of XCL1 mediates medullary accumulation of thymic dendritic cells and contributes to regulatory T cell development. J Exp Med 208:383-94, Crozat K, Guiton R, Contreras V et al. The XC chemokine receptor 1 is a conserved selective marker of mammalian cells homologous to mouse CD8alpha+ dendritic cells. J Exp Med 207: , Bachem A, Guttler S, Hartung E et al. Superior antigen cross-presentation and XCR1 expression define human CD11c+CD141+ cells as homologues of mouse CD8+ dendritic cells. J Exp Med 207: , Ferris ST, Carrero JA, Mohan JF, Calderon B, Murphy KM, Unanue ER. A minor subset of batf3-dependent antigen-presenting cells in islets of langerhans is essential for the development of autoimmune diabetes. Immunity 41:657-69,

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