title: Recombination activating gene-2 regulates CpG-mediated interferon-α production in mouse bone marrow-derived plasmacytoid dendritic cells.
abstract: Using mice that lack recombination activating gene-2 (Rag2), we have found that bone marrow-derived plasmacytoid dendritic cells (pDCs) as main producers of interferon-α (IFNα) require Rag2 for normal development. This is a novel function for Rag2, whose classical role is to initiate B and T cell development. Here we showed that a population of common progenitor cells in the mouse bone marrow possessed the potential to become either B cells or pDCs upon appropriate stimulations, and the lack of Rag2 hindered the development of both types of progeny cells. A closer look at pDCs revealed that Rag2⁻/⁻ pDCs expressed a high level of Ly6C and were defective at producing IFNα in response to CpG, a ligand for toll-like receptor 9. This phenotype was not shared by Rag1⁻/⁻ pDCs. The induction of CCR7, CD40 and CD86 with CpG, however, was normal in Rag2⁻/⁻ pDCs. In addition, Rag2⁻/⁻ pDCs retained the function to promote antibody class switching and plasma cell formation through producing IL-6. Further analysis showed that interferon regulatory factor-8, a transcription factor important for both IFNα induction and pDC development, was dysregulated in pDCs lacking Rag2. These results indicate that the generation of interferon response in pDCs requires Rag2 and suggest the lymphoid origin of bone marrow-derived pDCs.
authors.affiliation: Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America. xinluo@vt.edu
authors.forename: Xin M
authors.initials: XM
authors.lastname: Luo
authors.forename: Margarida Y Y
authors.initials: MY
authors.lastname: Lei
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D051940:B7-2 Antigen / Q000378:metabolism; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D019013:CD40 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism*; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D016130:Immunophenotyping; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism; D016898:Interferon-alpha / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D054400:Receptors, CCR7 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000378:metabolism*; D000074010:Bone Marrow Stromal Antigen 2
chemical_list: D015703:Antigens, CD; D051940:B7-2 Antigen; D019013:CD40 Antigens; D004268:DNA-Binding Proteins; D050838:Interferon Regulatory Factor-3; D016898:Interferon-alpha; D008562:Membrane Glycoproteins; D009838:Oligodeoxyribonucleotides; D054400:Receptors, CCR7; D051217:Toll-Like Receptor 9; C513868:BST2 protein, mouse; D000074010:Bone Marrow Stromal Antigen 2; C515371:Ccr7 protein, mouse; C526902:CpG ODN 2216; C494233:Irf3 protein, mouse; C499308:Rag2 protein, mouse