Investigation of regulatory mechanisms for homeostasis and activation of lymphocyte

• Project/Area Number: 16109004
• Research Category: Grant-in-Aid for Scientific Research (S)
• Allocation Type: Single-year Grants
• Research Field: Immunology
• Research Institution: The University of Tokyo (2004-2005, 2008); University of Toyama (2006-2007)
• Principal Investigator: TAKATSU Kiyoshi The University of Tokyo, 大学院・医学薬学研究部, 教授 (10107055)
• Co-Investigator(Kenkyū-buntansha): TAKAKI Satoshi 国立国際医療センター, 研究所, 部長 (10242116) ; NAGAI Yoshinori 富山大学, 大学院・医学薬学研究部, 准教授 (30431761) ; KOURO Taku (独)医薬基盤研究所, 免疫応答制御プロジェクト, プロジェクトリーダー (90372424) ; TAMURA Toshiki 国立感染症研究所, ハンセン病研究センター, 室長 (40291306) ; 刈米 アイ 東京大学, 医科学研究所, 助教 (50114450)
• Project Period (FY): 2004 – 2007
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥99,450,000 (Direct Cost: ¥76,500,000、Indirect Cost: ¥22,950,000); Fiscal Year 2007: ¥11,050,000 (Direct Cost: ¥8,500,000、Indirect Cost: ¥2,550,000); Fiscal Year 2006: ¥22,100,000 (Direct Cost: ¥17,000,000、Indirect Cost: ¥5,100,000); Fiscal Year 2005: ¥27,690,000 (Direct Cost: ¥21,300,000、Indirect Cost: ¥6,390,000); Fiscal Year 2004: ¥38,610,000 (Direct Cost: ¥29,700,000、Indirect Cost: ¥8,910,000)
• Keywords: 免疫学 / 自然免疫 / インターロイキン / アダプター分子 / クラススイッチ変換 / リンパ球 / インターロイキン5 / B-1細胞 / クラススイッチ / 結核菌 / 造血幹細胞 / IL-5 / Bリンパ球 / IgA / クラススイッチ組換え / Lnk / APS

Research Abstract

Bリンパ球のホメオスターシスと活性化の動態を制御するIL-5とLnkアダプターファミリー分子に焦点をあて、B-1細胞の恒常性維持やB-2細胞のIgHクラススイッチ組み換え、造血幹細胞増殖の制御にどのように関わるか明らかにして、Tリンパ球の分化との関係を分子レベルで明らかにする。

Research Products

• [Journal Article] Role of IL-5 in the Immune response to inflammation (2009)
  • Author(s): Takatsu K, Kouro T, Nagai Y
  • Journal Title: Adv. Immunol 101 Pages: 191-236
• [Journal Article] Toll-like receptor 7 cooperates with IL-4 in activated B cells through antigen receptor or CD38 and induces class switch recombination and IgG1 production (2009)
  • Author(s): Tsukamoto Y, Nagai Y, Kariyone A, Shibata T, Kaisho T, Akira S, Miyake K, Takatsu K
  • Journal Title: Mol. Immunol 46 Pages: 1278-1288
• [Journal Article] Initiation of the adaptive immune response to M. tuberculosis depends on antigen production in the local lymph node, not the lungs (2008)
  • Author(s): Wolf, AJ, Desvignes L, Linas B, Banaiee N, Tamura T, Takatsu K, Ernst JD
  • Journal Title: J. Exp. Med 205 Pages: 105-115
• [Journal Article] IL-5 and eosino-philia (2008)
  • Author(s): Takatsu K, Nakajima H
  • Journal Title: Curr. Opin. Immunol 20 Pages: 288-295
• [Journal Article] Deterget-resistant association of CD38 with membrane components for the triggering the B cell survival signal is associated with a comformational change of CD38 (2008)
  • Author(s): Hara-Yokoyama, M., et. al.
  • Journal Title: Int. Immunopharmacol 8 Pages: 59-70
  • Peer Reviewed
• [Journal Article] IL-5-induced eosinophils can suppress the antigen-induced immune response via a TGF-β-dependent mechanism (2007)
  • Author(s): Nakagome K, Dohi M, Okunishi K, Taanaka R, T. Kouro T, Kano MR, Miyazono K, Miyazaki J, Takatsu K, Yamamoto K
  • Journal Title: J. Immunol 179 Pages: 284-294
• [Journal Article] Instruction of CD4^+ T cell fate to T-bet expression and Th1 development by Th1-inducing peptide : roles of T cell receptor-mediated signals (2007)
  • Author(s): Ariga H, Shimohakamada Y, Tokunaga T, Kikuchi T, Nakata M, Kariyone A, Tamura T, Takatsu K
  • Journal Title: Immunology 122 Pages: 210-221
• [Journal Article] Nasal cholera toxin elicits IL-5 and IL-5 receptor alpha chain expressing CD5+ B cells for innate mucosal S-IgA antibody response (2007)
  • Author(s): Kataoka, K., et. al.
  • Journal Title: Journal of Immunology 178 Pages: 6058-6065
  • Peer Reviewed
• [Journal Article] Lnk negatively regulates self-renewal of hematopoietic stem cells by modifying thrombopoietin-mediated signal transduction (2007)
  • Author(s): Seita, J., et. al.
  • Journal Title: Proc. Natl. Acad. Sci. USA 104 Pages: 2349-2354
  • Peer Reviewed
• [Journal Article] IL-5 induced eosinophils can suppress the antigen-induced immune response via a TGF-beta-dependent mechanism (2007)
  • Author(s): Nakagome, K., et. al.
  • Journal Title: Journal of Immunology 179 Pages: 284-294
  • Peer Reviewed
• [Journal Article] A protein associated with toll-like receptor 4 (PRAT4A) is required for TLR-dependent immune responses (2007)
  • Author(s): Takahashi, K., et. al.
  • Journal Title: Journal of Experimenatl Medicine 204 Pages: 2963-2976
  • Peer Reviewed
• [Journal Article] Role of cytokines in allergic airway inflammation (2007)
  • Author(s): Nakajima, H., et. al.
  • Journal Title: Int. Arch. Allergy Immunol. 142 Pages: 265-273
  • Peer Reviewed
• [Journal Article] Crosstalk between neovessels and mural cells directs the site-specific Expression of MT1-MMP to endothelial tip cells (2007)
  • Author(s): Yana, I., et. al.
  • Journal Title: Journal of Cell Science 120 Pages: 1607-1614
  • Peer Reviewed
• [Journal Article] Interleukin-5 regulates genes involved in B cell terminal maturation (2006)
  • Author(s): Horikawa K, Takatsu K
  • Journal Title: Immunology 118 Pages: 497-508
• [Journal Article] Enhanced engraftment of hematopoietic stem/progenitor cells by the transient inhibition of an adaptor protein (2006)
  • Author(s): Takizawa H, Kubo-Akashi C, Nobuhisa I, Kwon S.-M., Iseki M, Taga T, Takatsu K, Takaki S
  • Journal Title: Lnk, Blood 107 Pages: 2968-2975
• [Journal Article] Interleukin 5 plays an essential role in elicitation of contact sensitivity through dual effects on eosinophils and B-1 cells (2006)
  • Author(s): Itakura, A., et. al.
  • Journal Title: Int. Arch. Allergy Immunol. 140Suppl1 Pages: 8-16
  • Peer Reviewed
• [Journal Article] A protein associated with toll-like receptor 4(PRAT4A)regulates cell surface expression of TLR4 (2006)
  • Author(s): Wakabayashi, Y., et. al.
  • Journal Title: Journal of Immunology 177 Pages: 1772-1779
  • Peer Reviewed
• [Journal Article] Interleukin-5 regulates genes involved in B-cell terminal maturation (2006)
  • Author(s): Horikawa, K., et. al.
  • Journal Title: Immunology 118 Pages: 497-508
  • Peer Reviewed
• [Journal Article] The order of expression of transcription factors directs hierarchical Specification of hematopoietic lineages (2006)
  • Author(s): Iwasaki, H., et. al.
  • Journal Title: Genes and Development 20 Pages: 3010-3021
  • Peer Reviewed
• [Journal Article] Augmented induction of CD8^+ cytotoxic T cell response and antitumor resistance by Th1-inducing peptide (2006)
  • Author(s): Kikuchi T
  • Journal Title: Immunology 117 Pages: 47-58
• [Journal Article] Enhanced engraftment of hematopoietic stem/progenitor cells by the transient inhibition of an intracellular adaptor protein, Lnk. (2006)
  • Author(s): Takizawa H
  • Journal Title: Blood (印刷中)
• [Journal Article] Role of IL-S in the elicitation of contact sensitivity that requires peritoneal B-1 cells and IgM production (2006)
  • Author(s): Itakura A
  • Journal Title: Int.Archives Allergy Immunol. (印刷中)
• [Journal Article] Spred-1 negatively regulates allergen-induced airway eosinophilia and hyperresponsiveness. (2005)
  • Author(s): Inoue H
  • Journal Title: J.Exp Med 201 Pages: 73-82
• [Journal Article] APS, an adaptor molecule containing PH and SH2 domains has a negative regulatory role in B cell proliferation. (2005)
  • Author(s): Iseki M
  • Journal Title: Biochem.Biophys.Res.Commun. 330 Pages: 1005-1013
• [Journal Article] Radioprotectiv 105-MD-1 links toll-like receptors 2 (TLR2) and TLR4-MD2 with antibody production to microbial membrane. (2005)
  • Author(s): Nagai Y
  • Journal Title: J.Immunol. 174 Pages: 7043-7049
• [Journal Article] Quantification of self-renewal capacity in a single hematopoietic stem cell from normal and Lnk-deficient mice. (2005)
  • Author(s): Ema H
  • Journal Title: Dev.Cell 8 Pages: 907-914
• [Journal Article] Identification of eosinophil lineage-committed progenitors in the murine bone marrow. (2005)
  • Author(s): Iwasaki H
  • Journal Title: J.Exp.Med. 201 Pages: 1891-1897
• [Journal Article] An hour alter immunization peritoneal B-1 cells are activated to migrate to lymphoid organs where within 1 day they produce IgM antibodies that initiate elicitation of contact sensitivity. (2005)
  • Author(s): Itakura A
  • Journal Title: J.Immunol. 175 Pages: 7170-7178
• [Journal Article] Interleukin 5:Modulator of innate and acquired immunity. (2005)
  • Author(s): Takatsu K
  • Journal Title: Inflamation Regeneration 25 Pages: 482-791
  • NAID: 10026499251
• [Journal Article] Spred-1 negatively regulates allergen-induced airway eosinophilia and hyperresponsiveness (2005)
  • Author(s): Inoue, H
  • Journal Title: J.Exp.Med 201 Pages: 73-82
• [Journal Article] Quantification of self-renewal capacity in single hematopoietic stem cells from normal and Lnk-deficient mice. (2005)
  • Author(s): Ema, H
  • Journal Title: Developmental Cell (印刷中)
• [Journal Article] APS, an adaptor molecule containing PH and SH2 domains has a negative regulatory role in B cell proliferation (2005)
  • Author(s): Iseki, M
  • Journal Title: Biochem.Biophys.Res.Commun (印刷中)
• [Journal Article] The role of antigenic peptide in CD4^+ T helper phenotype development in a T cell receptor transgenic model (2004)
  • Author(s): Tamura T, Ariga H, Kinashi T, Uehara S, Kikuchi T, Nakada M, Tokunaga T, Kariyone A, Saito T, Kitamura T, Maxwell G, Takaki S, Takatsu K
  • Journal Title: Int. Immunol 15 Pages: 1691-1699
  • NAID: 10014207554
• [Journal Article] The role of IL-5 for mature B-1 cells in homeostatic proliferation, cell survival, and Ig production (2004)
  • Author(s): Moon B.-G., Takaki S, Miyake K, Takatsu K. J. Immunol
  • Journal Title: J. Immunol 172 Pages: 6020-6029
• [Journal Article] Negative regulatory role of APS, adaptor molecule containing PH and SH2 domains in B-1 cells and B cell receptor-mediated proliferation. (2004)
  • Author(s): Iseki, M
  • Journal Title: Mol.Cell.Biol. 24 Pages: 2243-2250
• [Journal Article] Roles of conserved family of adaptor proteins, Lank, SH2-B and APS for mast cell development growth and functions : APS-deficiency causes impaired degranulation. (2004)
  • Author(s): Kudo-Akashi, C
  • Journal Title: Biochem.Biophys.Res.Commun 315 Pages: 356-362
• [Journal Article] The role of IL-5 for mature B-1 cells in homeostatic proliferation, cell survival, and Ig Production. (2004)
  • Author(s): Moon, B-G
  • Journal Title: J.Immunol. 172(10) Pages: 6020-6029
• [Journal Article] Btk enhances transcriptional co-activation activity of BAM11, a Btk associated molecule of a SWI/SNF complexes. (2004)
  • Author(s): Hirano, M
  • Journal Title: Int.Immunol. 16 Pages: 747-757
• [Journal Article] Role of IL-5 and eosinophils in allergen-induced airway remodeling in mice (2004)
  • Author(s): Tanaka, H
  • Journal Title: Am.J.Resp.Cell.MOl.Biol 31 Pages: 62-68
• [Journal Article] Abrogation of autoimmune disease in Lyn-deficient mice by the deletion of IL-5 receptor α chain gene. (2004)
  • Author(s): Moon, B-G
  • Journal Title: Cell.Immunol 228 Pages: 110-118
• [Journal Article] Transgene-mediated over-expression of IL-5 inhibits autoimmune disease, but increases the risk of B-cell chronic lymphocyt-c leukemia in a model of murine lupus. (2004)
  • Author(s): Wen, X
  • Journal Title: Eur.J.Immunol 34 Pages: 2740-2749
• [Journal Article] The role of antigenic peptide in CD4^+ T helper phenotype development in a T cell receptor transgenic model (2004)
  • Author(s): Tamura. T
  • Journal Title: Int.Immunol 15 Pages: 1691-1699
  • NAID: 10014207554
• [Journal Article] Src homology 2-containing 5-inositol phosphatase (SHIP) suppresses an early stage of lymphoid cell development through elevated interleukin-6 production by myeloid cells in bone marrow (2004)
  • Author(s): Nakamura, K
  • Journal Title: J.Exp.Med 199 Pages: 243-254
• [Presentation] Role of IL-5 in the allergic inflammation (2007)
  • Author(s): Takatsu, K.
  • Organizer: World Allergy Congress 2007
  • Place of Presentation: Bangkok
  • Year and Date: 2007-12-14
• [Presentation] Interleukin-5 and its receptor system in bealth and disease (2007)
  • Author(s): Takatsu, K.
  • Organizer: International Eosinophil Society 2007
  • Place of Presentation: Snowbirds,UT
  • Year and Date: 2007-07-21
• [Presentation] Molecular basis of IL-5 and its receptor system in the immune system and inflammation (2007)
  • Author(s): Takatsu, K.
  • Organizer: Bio WA-MedImmune Joint Seminar
  • Place of Presentation: Rockeville, MD
  • Year and Date: 2007-07-16
• [Presentation] Control of cell adhesion and migration in B lymphocytes and hematopoietic progenitors by Lnk, a negative regulator of cytokine signaling (2007)
  • Author(s): Takaki S, Iwasaki Y, Kubo C, Takizawa H, Takatsu K
  • Organizer: 13th International Congress of Immunology
  • Place of Presentation: Rio de Janeiro, Brazil
• [Presentation] Lnk, An Adaptor Protein, Modulates Signals mediated through integrins and cytokine receptors in hematopoietic progenitors (2007)
  • Author(s): Takizawa H, Eto K, Nakauchi H, Takatsu K, Takaki S
  • Organizer: 13th International Congress of Immunology
  • Place of Presentation: Rio de Janeiro, Brazil
• [Presentation] Genes involved in Btk-dependent pro-B to pre-B transition, Keystone Symposia (2007)
  • Author(s): Ikutani M, Kouro T, Takaki S, Takatsu K
  • Organizer: Banff
  • Place of Presentation: Canada
• [Presentation] P25CD4^+T細胞活性化とクロスプライミング増強の解析 (2007)
  • Author(s): 刈米アイ、田村敏生、高津聖志
  • Organizer: 第37回日本免疫学会学術集会
  • Place of Presentation: 東京
• [Presentation] Control of Dendritic Cell Production by Lnk/SH2B3 Adaptor Protein, a Negative Regulator of Lymphohematopoiesis (2007)
  • Author(s): Iwasaki Y, Takizawa H, Yamamoto K, Takatsu K, Takaki S
  • Organizer: 第37回日本免疫学会学術集会
  • Place of Presentation: 東京
• [Presentation] Dynamic expression patterns of Lnk, a negative regulatory adaptor in lymphohematopoiesis revealed by generating a GFP knock-in reporter mice (2007)
  • Author(s): Katayama H, Ikutani M, Yoshida N, Takatsu K, Takaki S
  • Organizer: 第37回日本免疫学会学術集会
  • Place of Presentation: 東京
• [Presentation] 免疫バイオ研究と創薬探索 (2007)
  • Author(s): 高津聖志
  • Organizer: 医療薬学フォーラム2007
  • Place of Presentation: 山形
• [Presentation] 免疫と炎症を制御するシグナル、IL-5の関与とその謎 (2007)
  • Author(s): 高津聖志
  • Organizer: 第16回東京免疫フォーラム(特別講演)
  • Place of Presentation: 東京
• [Presentation] Toll-like receptors on hematopoietic ptogenitor cells stimulate innate immune system replenishment. (2006)
  • Author(s): Nagai, Y.
  • Organizer: Joint Meeting of the Society for Leukocyte Biology and the International Endotoxin and Innate Immunity Society
  • Place of Presentation: San Antonio, TX
  • Year and Date: 2006-11-10
• [Presentation] Hematopoietic stem/progenitor cells express functional Toll-like receptors that potentially stimulate replenishment of the innate immune system. (2006)
  • Author(s): Nagai, Y.
  • Organizer: The American Association of Immunologists Annual Meeting
  • Place of Presentation: Boston, MA
  • Year and Date: 2006-05-15
• [Presentation] Delayed initiation of adaptive immunity to Mycobacterium tuberculosis is due to delayed CD4+T cell priming. (2006)
  • Author(s): Wolf, B.A.
  • Organizer: Joint Meeting of the Society for Leukocyte Biology and the International Endotoxin and Innate Immunity Society
  • Place of Presentation: Boston, MA
  • Year and Date: 2006-05-14
• [Presentation] Role of Toll-like receptor in the induction of activation-induced cytidine deaminase(AID) and class switch recombination. (2006)
  • Author(s): Takatsu, K.
  • Organizer: The American Association of Immunologists Annual Meeting
  • Place of Presentation: Boston, MA
  • Year and Date: 2006-05-13
• [Presentation] Toll-like receptors on hematopoietic progenitor cells stimulate innate immune system replenishment (2006)
  • Author(s): Nagai Y, Garrett KP, Ohta S, Bahrun U, Kouro T, Akira S, Takastu K, Kincade PW
  • Organizer: A Joint Meeting of the Society of Leukocyte Biology and the International Endotoxin and Innate Immunity Society
  • Place of Presentation: San Antonio, TX
• [Presentation] Prospective isolation of human eosinophil lineage-commitment progenitors revealed that the eosinophil differentiation pathway is different in human and mouse hematopoiesis (2006)
  • Author(s): Mori Y, Iwasaki H, Yoshimoto G, Okeda A, Miyamoto T, Mizuno S, Harada M, Takatsu K, Akashi A
  • Organizer: Am. Soc. Hematol
  • Place of Presentation: San Antonio, TX
• [Presentation] Ag85B and its peptide of Mycobacterium tuberculosis as a potent immunomodulator: Robust induction of Th1 response and cross-priming (2006)
  • Author(s): Takatsu, K
  • Organizer: The 13th East Asian Joint Symposium-From Genes to Therapeutics
  • Place of Presentation: Seoul
• [Presentation] Immunobiology of Ag85B and Peptide-25 of Mycobacterium tuberculosis (2006)
  • Author(s): Takatsu, K
  • Organizer: 8th Awaji Forum on Infection and Immunity
  • Place of Presentation: Awaji Island
• [Presentation] Role of Toll-like receptor in the induction of activation-induced cytidine deaminase(AID)and class switch recombination Immunology 2006 (2006)
  • Author(s): Takatsu K, Tsukamoto Y, Kaisho M
  • Organizer: AAI Annual Meeting
  • Place of Presentation: Boston MA
• [Presentation] Expression of IL-5 receptor a chain on B-1 cell progression (2006)
  • Author(s): Kouro T, Ikutani M, Takatsu K
  • Organizer: 第36回日本免疫学会学術集会
  • Place of Presentation: 大阪
• [Presentation] Ag85B由来Peptide-25によるクロスプライミング増強効果の解析 (2006)
  • Author(s): 刈米アイ、田村敏生、高津聖志
  • Organizer: 第36回日本免疫学会学術集会
  • Place of Presentation: 大阪
• [Presentation] Toll-like receptors on hematopoietic progenitor cells stimulate innate immune system replenishment (2006)
  • Author(s): Nagai Y, Garrett KP, Ohta S, Bahrun U, Kouro T, Akira S, Takatsu K, Kincade PW
  • Organizer: 第36回日本免疫学会学術集会
  • Place of Presentation: 大阪
• [Presentation] Ag85Bとそのペプチドによる免疫制御 : Th1誘導とクロスプライミング増強 (2006)
  • Author(s): 高津聖志
  • Organizer: 第34回BCG・BRM療法研究会
  • Place of Presentation: 東京
• [Presentation] TCRシグナルを介するTh1分化における転写因子T-betの役割 : T-betノックアウトマウスを用いた解析 (2005)
  • Author(s): 下袴田陽子、徳永岳史、仲田真己代、有賀晴之、刈米アイ、田村敏生、高津聖志
  • Organizer: 第35回日本免疫学会学術集会
  • Place of Presentation: 横浜
• [Book] TLRシグナルとクラススイッチ組換え臨床免疫・アレルギー科49 (2008)
  • Author(s): 長井良憲, 塚本裕美子, 高津聖志
  • Publisher: 科学評論社
• [Book] Ag85BによるTh1誘導と免疫腑活活性、MINOPGAGEN MEDICAL REVIEW 52 (2007)
  • Author(s): 高津聖志
  • Publisher: ミノファーゲン製薬
• [Book] 免疫とは「臨床アレルギー学 アレルギー専門医研修のために改訂第3版 (2007)
  • Author(s): 長井 良憲、高津 聖志
  • Total Pages: 3
  • Publisher: 南江堂
• [Book] IL-5ものがたり(連載第3回)、感染・炎症・免疫、36 (2006)
  • Author(s): 高津聖志
  • Publisher: 医薬の門社
• [Book] 7サイトカイン、予防医学事典(松島剛治、酒井敏行、石川昌、稲寺秀邦編) (2005)
  • Author(s): 高津聖志
  • Publisher: 朝倉書店
• [Book] タンパク質実験のための抗体実験マニュアル(実験医学別冊)(高津聖志、三宅健介、山元弘、瀧信介編)(基礎科学を支える研究ツールとしての抗体に関する基礎知識) (2004)
  • Author(s): 小池正道、高津聖志
  • Publisher: 羊土社
• [Book] インターロイキン5、サイトカイン・ケモカインのすべて(笠倉新平、松島綱治編) (2004)
  • Author(s): 高津聖志
  • Publisher: 日本医学館