in vivo

More documents

Recommendations

Info

Laboratory for Immune Regulation CD1d-restricted natural killer T (NKT) cells express both a single invariant Vα14 antigen receptor and NK receptors such as NK1.1, and are therefore known as Vα14 NKT cells. Because of this unique combination of receptors, the NKT cells occupy a distinctive intermediary position between innate and acquired immunity. Furthermore, because of their ability to quickly release large amount of cytokines, such as interferon (IFN)-γ and IL-4, and their apparent self-reactivity, NKT cells have been hypothesized to play important roles in the initiation and regulation of many types of immune responses. In fact, NKT cells mediate strong adjuvant activity by their IFN-γ production and augment anti-tumor immune responses. Therefore, we have started phase I/IIa clinical trial on NKT cell-targeted therapy for advanced lung cancer patients. On the other hand, NKT cells have been implicated in various autoimmune diseases development such as SLE, type I diabetes, systemic sclerosis, and in allergic diseases such as asthma. Our group studies the regulation of immune functions and responses, both beneficial and harmful, mediated by NKT cells. We hope to contribute to the development of new strategies for human immune therapy. Identification of IL-17RB as a novel marker for the IL-13 producing iNKT subset important for respiratory syncytial virus-dependent airway hyperreactivity development Group director Masaru Taniguchi Senior Research Scientist Research Scientists Visiting Scientists Technical Staffs Student Trainees : Hiroshi Watarai : Ryusuke Nakagawa Takuya Tashiro Nyambayar Dashtsoodol : Miyuki Omori-Miyake Takashi Tsujimoto : Sakura Sakata Etsuko Sekine Yuko Nagata Sayo Inoue Naoko Tago : Asuka Terashima Naomi Hongo Tomoki Chiba Asthma is an immunological disease that has increased dramatically in prevalence over the past half a century. In industrialized countries, the incidence of asthma has nearly doubled since 1980 and one in five to ten individuals is affected. Asthma is caused by environmental factors, such as allergen exposure and infection, in genetically predisposed individuals. Respiratory syncytial virus (RSV) infection causes bronchiolitis especially in infants and children, which is an important risk factor for the development of chronic asthma. However, the molecular mechanisms by which RSV infection increases asthma susceptibility still remain unclear. We have discovered that RSV infection induces IL- 17E/IL-25, which triggers NKT cell activation and leads to airway hypersensitive reaction (AHR), a cardinal feature of asthma. Based on CD4/CD8 expression, NKT cells can be divided into two populations, CD4 + and CD4 - CD8 - double negative (DN). These two Assistant : Norie Takeuchi 62
Figure 1 Mechanisms in RSV-induced AHR induction NKT cell subsets have distinct functions, such as helper and cytotoxic functions, respectively. We have found that IL-17RB, one of the IL-17 receptor family members and a receptor for IL-17E/IL-25, is preferentially expressed on a fraction of NKT cells. None of the other leukocyte populations tested were IL-17RB+ and, among NKT cells, about one third of CD4 + cells, but not the DN cells, expressed the receptor. Moreover, CD4 + IL-17RB + NKT cells proliferate and produce predominantly Th2 cytokines and chemokines (IL-13, IL-4, TARC, MDC, ECF-L) in an IL-17E/IL- 25-dependent manner and induce AHR in mice. These results strongly suggest that CD4 + IL- 17RB + NKT cells with Th2-like phenotype may have a crucial role, distinct from that of Th2 cells, in the pathogenesis of asthma. A novel plasmacytoid dendritic cellspecific receptor, PDC-TREM, is responsible for augmented production of type I interferons Successful host defense against viral pathogens depends largely on inhibition of viral replication during the early stages of infection by rapid and robust production of type I interferons (IFNs). Several viral recognition molecules have been identified, including retinoic-acid-inducible gene I (RIG-I) and melanoma-differentiationassociated gene 5 (MDA5), that mediate type I IFN production in conventional dendritic cells (CDCs). Plasmacytoid dendritic cells (PDCs) are also specialized producers of type I IFNs, however, the mechanism(s) underlying type I IFN production by these cells remain unclear. Although triggering through toll-like receptors (TLRs) activates PDCs to produce type I IFNs, optimal production does not depend solely on TLRs, but requires TLR-mediated secondary events. Type I IFN-α/β receptor (IFNAR)-deficient PDCs fail to produce type I IFNs in response to TLR agonists, indicating that IFNAR-signaling itself, in a positive feedback loop, is one of these TLR-mediated secondary events. Constitutive expression of IFN regulatory factor (IRF)-7 in PDCs is also thought to augment type I IFN production, however, IRF-7 is detected in various cell types, and the level of IRF-7 expression does not correlate with the amount of type I IFN produced. Thus, other signaling events must be involved in type I IFN production following TLR triggering. We have identified a novel cell surface molecule, PDC-TREM, a member of the triggering receptor expressed on myeloid cells (TREM) family, which is preferentially expressed on TLR-stimulated PDCs. Surface expression of PDC-TREM requires not only TLR- but also IFNAR-signaling. PDC-TREM forms a molecular complex with another transmembrane protein, Plexin-A1 (PlxnA1). The PlxnA1 ligand Sema6D induces robust production of type I IFNs, and when the association of PDC-TREM with PlxnA1 or the expression of PDC-TREM on the cell surface is prevented, both type I IFN production and PDC-TREM-induced signaling events are inhibited. Therefore, TLR- and IFNAR-signaling are responsible for expression of PDC-TREM, whose signaling cascade further augments production of type I IFNs. Figure 2 PDC-TREM-dependent typeI IFN production from plasmacytoid dendritic cells Recent publications Watarai H., Nakagawa R., Omori-Miyake M., Nyambayar D., Taniguchi M. Methods for detection, isolation, and culture of mouse and human invariant NKT cells. Nat. Protoc. 3, 70-78 (2008) Watarai H, Sekine E, Inoue S, Nakagawa R, Kaisho T, Taniguchi M. PDC-TREM, a plasmacytoid dendritic cell-specific receptor, is responsible for augmented production of type I interferon. Proc Natl Acad Sci U S A. 105, 2993-2998 (2008). Harada M., Magara-Koyanagi K., Watarai H., Nagata Y., Ishii Y., Kojo S., Horiguchi S., Okamoto Y., Nakayama T., Suzuki N., Wen- Chen Y., Akira S., Kitamura H., Ohara O., Seino K., Taniguchi M. IL-21–induced Bε cell apoptosis mediated by natural killer T cells suppresses IgE responses. J. Exp. Med. 203, 2929-2937 (2006) Yasunami Y., Kojo S., Kitamura H., Toyofuku A., Satoh M., Nakano M., Nabeyama K., Nakamura Y., Matsuoka N., Ikeda S., Tanaka M., Ono J., Nagata N., Ohara S., Taniguchi M. Vα14 NKT cell-triggered IFN-γ production by Gr-1+CD11b+ cells mediates early graft loss of syngeneic transplanted islets. J. Exp. Med. 202, 913-918 (2005) Inoue K., Wakao H., Ogonuki N., Miki H., Seino K., Nambu-Wakao R., Noda S., Miyoshi H., Koseki H., Taniguchi M., Ogura A. Generation of cloned mice by direct nuclear transfer from natural killer T cells. Curr. Biol. 15, 1114-1118 (2005) 63
Page 2 and 3:
Special Advisor Kimishige Ishizaka
Page 4 and 5:
i v Organization Director’s Repor
Page 6 and 7:
Director’s Report This is the fou
Page 8 and 9:
RCAI research retreat program. Prev
Page 10 and 11:
Haruhiko Koseki Good housekeeping A
Page 12 and 13:
Hiroshi Ohno Cell fusion may create
Page 14 and 15:
Tsuneyasu Kaisho Halting the inflam
Page 16 and 17:
Takashi Saito Signaling simplified
Page 18 and 19:
Makio Tokunaga Looking beneath the
Page 20 and 21: Tomohiro Kurosaki Immune cells stim
Page 22 and 23: Ichiro Taniuchi How cells switch fr
Page 24 and 25: Shin-ichiro Fujii On the road to a
Page 26 and 27: Award Winners 2007 Shohei Hori and
Page 28 and 29: found a factor called PDLIM2 that l
Page 30 and 31: 2007 Excellent Paper Award and Exce
Page 32 and 33: Laboratory for Developmental Geneti
Page 34 and 35: Research Unit for Lymphocyte Clonin
Page 36 and 37: Laboratory for Lymphocyte Developme
Page 38 and 39: Laboratory for Transcriptional Regu
Page 40 and 41: Laboratory for Cell Signaling The l
Page 42 and 43: Research Unit for Single Molecule I
Page 44 and 45: Laboratory for Lymphocyte Different
Page 46 and 47: Research Unit for Molecular Systems
Page 48 and 49: Laboratory for Epithelial Immunobio
Page 50 and 51: Laboratory for Mucosal Immunity Ver
Page 52 and 53: Laboratory for Immunological Memory
Page 54 and 55: Laboratory for Immune Diversity Tea
Page 56 and 57: Laboratory for Host Defense Host de
Page 58 and 59: Laboratory for Infectious Immunity
Page 60 and 61: Laboratory for Dendritic Cell Immun
Page 62 and 63: Laboratory for Innate Cellular Immu
Page 64 and 65: Research Unit for Therapeutic Model
Page 66 and 67: Laboratory for Autoimmune Regulatio
Page 68 and 69: Research Unit for Immune Homeostasi
Page 72 and 73: Laboratory for Immunchaperones Unfo
Page 74 and 75: Laboratory for Cytokine Signaling D
Page 76 and 77: Laboratory for Signal Network cells
Page 78 and 79: Laboratory for Immunogenetics The m
Page 80 and 81: Research Unit for Immune Tissue Eng
Page 82 and 83: Research Unit for Human Disease Mod
Page 84 and 85: Research Unit for Cellular Immunoth
Page 86 and 87: Laboratory for Vaccine Design Team
Page 88 and 89: Laboratory for Immunogenomics Group
Page 90 and 91: Research Unit for Immunoinformatics
Page 92 and 93: Laboratory for Lymphocyte Developme
Page 94 and 95: Research Unit for Immunoepigenetics
Page 96 and 97: Central Facilities Central Faciliti
Page 98 and 99: RIKEN Special Postdoctoral Research
Page 100 and 101: Primary Immunodeficiencies Network
Page 102 and 103: Collaboration with Foreign Institut
Page 104 and 105: Collaboration with Foreign Institut
Page 106 and 107: RCAI Advisory Council Throughout th
Page 108 and 109: International Progams Short-term Le
Page 110 and 111: RCAI International Summer Program (
Page 112 and 113: RCAI-JSI International Symposium 20
Page 114 and 115: 2 nd JSI-RCAI Workshop Lessons lear
Page 116 and 117: Guidance session for adjunct gradua
Page 118 and 119: In Memory of Konomi Nakamura Satosh
Page 120 and 121:
Publications FY2007 Apr. 2007- Mar.
Page 122 and 123:
55. Miyake, Y., Asano, K., Kaise, H
Page 124 and 125:
Invited Presentations Meeting RIKEN
Page 126 and 127:
The 37th Annual Meeting of the Japa
Page 128 and 129:
14-Nov-2007 Antibodies and their re
Page 130 and 131:
Original Photos of the Cover and Fr
show all

in vivo

Create successful ePaper yourself

Delete template?

Save as template?