東北大学加齢医学研究所 加齢医学研究拠点 | Institute of Development, Aging and Cancer, Tohoku University

研究活動

遺伝子導入研究分野

教授 医博 高井 俊行
講師 博士(医学) 乾 匡範
非常勤講師 博士(医学) 中村 晃
非常勤講師 博士(医学) 森本 素子
非常勤講師 博士(障害科学) 坂本 譲
助教 博士(医学) 伊藤 亜里
技術補佐員   飛内 章子
事務補佐員   中村 孝子
遺伝子導入研究分野のホームページへ


私たち遺伝子導入研究分野は加齢医学研究所の改組に伴って平成5年に新設されました。現在の研究室は平成9年10月に稼働を始めてからおよそ12年半経ちますが、東北大学の標榜する門戸開放・研究中心主義を念頭に置きながら、歴史や伝統に縛られることなく、以下のテーマのもと、自由で活発な研究活動を行っています。当研究室の様子をさらに詳しく知りたい方はこちら(http://www2.idac.tohoku.ac.jp/dep/expimmu/index.html )を参照してください。

私達の研究目標は、Immunoglobulin-Like Receptor(IgLR)と称される免疫系の受容体 分子群(図1)、たとえばFc レセプター(FcR)分子群やPaired Immunoglobulin-Like Receptor (PIR)分子群などの遺伝子ターゲティングマウスの開発(図2)と生理機能の解明を通し、アレルギー、自己免疫疾患、癌、移植免疫病など、関連する疾患の発症機構を解明することであり、これらの治療方法の開発へ向けた新規な提案を行っていきたいと考えています。同時に、これらの研究を志す大学院生を広く受け入れ、私達の研究テーマを責任持って分担してもらうことで、研究者としての素養と実力を養ってもらいたいと考えています。

異物が侵入したときに生体が作り出す中和抗体と結合するFcRは、多様な構造を持った細胞膜上のレセプター分子群です(図1)。これらは特に炎症や自己免疫疾患の発症に関与していると考えられてきました。特にヒトで、最も微量でアレルギーを引き起こす抗体であるIgEは、そのレセプターであるFcεRIと結合し、抗原によって刺激されてアレルギー発症の引き金を引くことは良く知られている例です。私たちはこのように多様なFcRがどのように免疫系に関わっているのかを解明するために、FcRおよびそのサブユニット分子の遺伝子を破壊されたマウス、いわゆるノックアウトマウの作成を行い、解析しました。その結果、このように多様なFcR分子群は免疫系に対して活性化の機能をもつタイプと、逆に抑制機能を示すものとに大別され、免疫応答を正と負の両方向にうまく調節していることが分かり、このバランスが崩れるとがアレルギーなどの発症につながることが示されました。この正と負の制御様式はアレルギーのみならず自己免疫疾患においても機能しています。

PIRはFcR群と遺伝子レベルで親戚関係にある分子です(図2)。 PIRはアレルギーや自己免疫疾患などの発症機構にどのように関わっているのでしょうか?私たちの研究では、抑制性レセプターであるPIR-Bを欠損したマウスではTh2型の応答、つまりアレルギーを起こしやすい性質を持つことが分かりました。さらにわたしたちはPIR-Bの免疫制御機構を解析する中で,これがMHCクラスIという,自己のマーカー分子を認識していることを解明しました。一方,抗体を産生するB細胞には,抗原特異的な抗体を産生するB2細胞と,抗原非特異的な自然抗体を産生するB1細胞があります(図3)。とりわけB1細胞は自己組織にも反応する自然抗体を産生することがわかっています(図2)。このB1細胞において,わたしたちはPIR-Bが細菌やウィルスなどを認識するToll様レセプターからのシグナル伝達を抑制することにより,自己反応性を制御していることを明らかにしました(図4)。

ごく最近になり,PIR-Bは神経軸索伸長阻害因子群とも結合することが他のグループにより示され,PIR-Bによる制御機構は単に免疫系にとどまらないことが示唆されています。わたしたちは今後,FcγRIIBやPIR-Bなどの免疫制御機構の全容を解明し,この制御機構の利用による免疫病の克服に向けた研究を展開して行きます。

図1
図1.免疫系を正と負に調節する典型的なIgLR分子であるFc受容体の仲間
ヒトとマウスの代表的なFcR分子群とそのリガンドを模式的に表した。FcγRIIBは代表的な抑制性受容体であり、細胞内に抑制モチーフITIM(immunoreceptor tyrosine-based inhibitory motif) を持つが、かたや活性化型受容体は活性化モチーフITAM(immunoreceptor tyrosine-based activation motif)を持つサブユニットFcRγ鎖と会合する。

図2
図2. 免疫系細胞を正と負に調節するPIR分子群
ヒトのLILRおよびマウスのPIR分子群の構造を模式的に表した。PIR-Bは抑制性受容体であり、細胞内に抑制モチーフITIMを持つが、かたや活性化型受容体のPIR-Aは活性化モチーフITAMを持つサブユニットFcRγ鎖と会合する。

図3
図3. B細胞における免疫寛容
B細胞には,抗原特異的な抗体を産生するB2細胞と、抗原非特異的な自然抗体を産生するB1細胞がある。B2細胞は骨髄において、自己組織に反応しないように選別される(免疫寛容)。一方、B1細胞は主に腹腔や胸腔内に存在しており、自己組織にも弱く反応する細胞が分化してしまう。

図4
図4. PIR-BによるTLR9シグナル伝達制御機構
リウマチ因子(Rheumatiod factor: RF)は、抗体のFc部分に対する自己抗体で、主にB1細胞によって産生される。このRF産生細胞の活性化にはToll-like receptor (TLR)9からの活性化シグナル伝達が必須であることが判明している。PIR-Bに会合するSHP-1はToll-like receptor (TLR) 9によって活性化されるBtkのリン酸化を抑制することにより、リウマチ因子(Rheumatiod factor: RF)産生を制御している。

研究業績(2000年以降の英文論文)
169. Inui M, Tazawa K, Kishi Y, Takai T. Platelets convert peripheral blood circulating monocytes to regulatory cells via immunoglobulin G and activating-type Fcg receptors.BMC Immunol. in press.
168. Kimura T, Endo S, Inui M, Saitoh S-i, Miyake K, Takai T. Endoplasmic protein Nogo-B (RTN4-B) interacts with GRAMD4 and regulates TLR9-mediated innate immune responses. J. Immunol. in press.
167. Inui M*, Hirota S*, Hirano K, Fujii H, Sugahara-Tobinai A, Ishii T, Harigae H, Takai T. (*equal contribution) Human CD43+ B cells are closely related not only to memory B cells phenotypically but also to plasmablasts developmentally in healthy individuals. Int Immunol. 2015 Mar 5. pii: dxv009.
166. Nehishi–Koga T, Gober HJ, Sumiya E, Komatsu N, Okamoto K, Sawa S, Suematsu S, Suda T, Sato K, Takai T, Takayanagi H. Immune complexes regulate bone metabolism through FcRγ signaling. Nat Commun in press.
165. Kobayashi M, Konishi H, Takai T, Kiyama H. A DAP12-Dependent Signal Promotes Pro-Inflammatory Polarization in Microglia Following Nerve Injury and Exacerbates Degeneration of Injured Neurons Glia in press.
164. Kanno A, Tanimura N, Ishizaki M, Ohko K, Motoi Y, Onji M, Fukui R, Shimozato T, Yamamoto K, Shibata T, Sano S, Sugahara-Tobinai A, Takai T, Ohto U, Shimizu T, Saitoh S, Miyake K. Targeting cell surface TLR7 for therapeutic intervention in autoimmune diseases. Nat Commun in press.
163. Kanari Y, Sugahara–Tobinai A, Takahashi H, Inui M, Nakamura A, Hirose S, Takai T.
Dichotomy in the FcγRIIB deficiency and autoimmune-prone SLAM haplotype clarifies the roles of the Fc receptor in development of autoantibodies and glomerulonephritis. BMC Immunol 2014, 15:47 http://www.biomedcentral.com/1471-2172/15/47  doi:10.1186/s12865-014-0047-y
162. Fukao S, Haniuda K, Nojima T, Takai T, Kitamura D. Gp49B-Mediated Negative Regulation of Antibody Production by Memory and Marginal Zone B Cells. J Immunol. 2014 Jul 15;193(2):635-44. doi: 10.4049/jimmunol.1302772.
161. Yasukawa S, Miyazaki Y, Yoshii C, Nakaya M, Ozaki N, Toda S, Kuroda E, Ishibashi K, Yasuda T, Natsuaki Y, Mi-ichi F, Iizasa E, Nakahara T, Yamazaki M, Kabashima K, Iwakura Y, Takai T, Saito T, Kurosaki T, Malissen B, Ohno N, Furue M, Yoshida H, Hara H. An ITAM-Syk-CARD9 signalling axis triggers contact hypersensitivity by stimulating IL-1 production in dendritic cells. Nat Commun 2014 5:3755. doi: 10.1038/ncomms4755.
160. Lo TH, Tseng KY, Tsao WS, Yang CY, Hsieh SL, Chiu AW, Takai T, Mak TW, Tarng DC, Chen NJ. TREM-1 regulates macrophage polarization in ureteral obstruction. Kidney Int. 2014; 86(6):1174-86. doi: 10.1038/ki.2014.205.
159. Kam TI, Song S, Gwon Y, Park H, Yan JJ, Im I, Choi JW, Choi TY, Kim J, Song DK, Takai T, Kim YC, Kim KS, Choi SY, Choi S, Klein WL, Yuan J, Jung YK. FcγRIIb mediates amyloid-β neurotoxicity and memory impairment in Alzheimer's disease. J Clin Invest. 2013 Jul 1;123(7):2791-802. doi: 10.1172/JCI66827. Epub 2013 Jun 10.
158. Tammaro A, Stroo I, Rampanelli E, Blank F, Butter LM, Claessen N, Takai T, Colonna M, Leemans JC, Florquin S, Dessing MC. Role of TREM1-DAP12 in renal inflammation during obstructive nephropathy. PLoS One. 2013 Dec 16;8(12):e82498. doi: 10.1371/journal.pone.0082498.
157. Montalvo V, Quigley L, Vistica BP, Boelte KC, Nugent LF, Takai T, McVicar DW, Gery I. Environmental factors determine DAP12 deficiency to either enhance or suppress immunopathogenic processes. Immunology 2013; 140(4):475-82. doi: 10.1111/imm.12158.
156. Matsumoto M, Sasaki Y, Yasuda K, Takai T, Muramatsu M, Yoshimoto T, Nakanishi K. IgG and IgE Collaboratively Accelerate Expulsion of Strongyloides venezuelensis in a Primary Infection. Infect. Immun., 81: 2518-27 (2013) doi: 10.1128/IAI.00285-13.
155. Kawano S, Lin Q, Amano H, Kaneko T, Nishikawa K, Tsurui H, Tada N, Nishimura H, Takai T, Shirai T, Takasaki Y, Hirose S. Phenotype conversion from rheumatoid arthritis to systemic lupus erythematosus by introduction of Yaa mutation into FcγRIIB-deficient C57BL/6 mice. Eur J Immunol. 2013 Mar;43(3):770-8. doi: 10.1002/eji.201243057. Epub 2013 Jan 25.
154. Tanaka J, Hirano K, Sakamoto Y, Sugahara-Tobinai A, Endo S, Ito-Matsuoka Y, Nakano A, Inui M, Nitschke L, Takai T. Intravenous immunoglobulin suppresses IL-10 production by activated B cells in vitro. Open J. Immunol. 2(4): 149-160, 2012 (DOI: 10.4236/oji.2012.24019)
153. Kuroki K, Hiorse K, Okabe Y, Fukunaga Y, Takahashi A, Shiroishi M, Kajikawa M, Tabata S, Nakamura S, Takai T, Koyanagi S, Ohdo S, Maenaka K. The long-term immunosuppressive effects of disulfide-linked HLA-G dimer in mice with collagen-induced arthritis. Human Immunol. Dec. 29, 2012 (doi:pii: S0198-8859(12)00688-X. 10.1016/j.humimm.2012.11.060)
152. Nakayama M, Kurokawa K, Nakamura K, Lee BL, Sekimizu K, Kubagawa H, Hiramatsu K, Yagita H, Okumura K, Takai T, Uderhill DM, Aderem A, Ogasawara K. Inhibitory receptor PIR-B is exploited by Staphylococcus aureus for virulence. J. Immunol.189: 5903-11, 2012. (doi: 10.4049/jimmunol.1201940)
151. Mitsuhashi Y, Nakamura A, Endo S, Takeda K, Yabe-Wada T, Nukiwa T, Takai T. Regulation of plasmacytoid dendritic cell responses by PIR-B. Blood 120: 3256-9. 2012. doi:10.1182/blood-2012-03-419093
150. Zangi L, Klionsky YZ, Yarimi L, Bacher-Lustig E, Edelshtein Y, Shezen E, Hagin D, Ito Y, Takai T, Reichi-Zeliger S, Lask A, Milstein O, Jung S, Shinder V, Reisner Y. Deletion of cognate CD8 T-cells by immature dendritic cells: a novel role for perforin, Granzyme A, TREM-1 and TLR7. Blood 120(8):1647-57, 2012 (doi: 10.1182/blood-2012-02-410803)
149. Wong WF, Kohu K, Nakamura A, Ebina M, Kikuchi T, Tazawa R, Tanaka K, Kon S, Funaki T, Sugahara-Tobinai A, Looi CY, Endo S, Funayama R, Kurokawa M, Habu S, Ishii N, Fkumoto M, Nakata K, Takai T, Satake M. Runx1 deficiency in CD4+ T cells causes fatal autoimmune inflammatory lung disease due to spontaneous hyperactivation of cells. J. Immunol. 2012; 188: 5408-5420; Epub 2 May 2012; doi: 10.4049/jimmunol.1102991
148. Kikuchi T, Kasuya R, Endo S, Nakamura A, Takai T, Metzler-Nolte N, Tohji K, and Balachandran J. Preparation of magnetite aqueous dispersion for magnetic fluid hyperthermia. J. Magn. Magn. Mater. 323: 1216-1222 (2011)
147. Nakayama M, Takeda K, Kawano M, Takai T, Ishii N, Ogasawara K. Natural killer (NK)-dendritic cell interactions generate MHC class II-dressed NK cells that regulate CD4+ T cells. Proc. Natl. Acad. Sci. USA. 108: 18360-18365 (2011).
146. Sato-Hayashizaki A, Ohtsuji M, Lin Q, Hou R, Ohtsuji N, Nishikawa K, Tsurui H, Sudo K, Ono M, Izui S, Shirai T, Takai T, Nishimura H, Hirose S.Presumptive role of 129 strain-derived Sle16 locus in rheumatoid arthritis in a new mouse model with Fcγ receptor type IIb-deficient C57BL/6 genetic background. Arthritis Rheum. 63: 2930-2938 (2011).
145. McCormick S, Shaler CR, Small CL, Horvath C, Damjanovic D, Brown EG, Aoki N, Takai T, Xing Z. Control of pathogenic CD4 T cells and lethal immunopathology by signaling immunoadaptor DAP12 during influenza infection. J Immunol. 187: 4280-4292 (2011).
144. Fujita Y, Takashima R, Endo S, Takai T, Yamashita T. The p75 receptor mediates axon growth inhibition through an association with PIR-B. Cell Death Dis. 2: e198 (2011).
143. Nakano-Yokomizo T, Tahara-Hanaoka S, Nakahashi-Oda C, Nabekura T, Tchao NK, Kadosaki M, Totsuka N, Kurita N, Nakamagoe K, Tamaoka A, Takai T, Yasui T, Kikutani H, Honda S, Shibuya K, Lanier LL, Shibuya A. The immunoreceptor adapter protein DAP12 suppresses B lymphocyte–driven adaptive immune responses. J Exp Med. 208:1661-1671 (2011).
142. Matsushita H, Endo S, Kobayashi E, Kobayashi K, Kitaguchi K, Kuroki K,
Soderhall A, Maenaka K, Nakamura A, Takai T. Differential but competitive binding of Nogo and MHCI to PIR-B provides an inhibition of cells. J. Biol. Chem. 286: 25739-25747 (2011).
141. Arita K, Endo S, Kaifu T, Kitaguchi K, Nakamura A, Ohmori H, Kohu K, Satake M, Takai T. Transcriptional activation of the Pirb gene in B cells by PU.1 and Runx3. J. Immunol. 186: 7050-7059 (2011).
140. Ma G, Pan PY, Eisenstein S, Divino CM, Lowell C, Takai T, Chen SH. Paired immunoglobulin like receptor-B regulates the suppressive function and fate of myeloid derived suppressor cells. Immunity 34: 385-395 (2011).
139. Fujita Y, Endo S, Takai T, Yamashita T. Myelin suppresses axon regeneration by PIR-B/SHP-mediated inhibition of Trk activity. EMBO J. 30: 1389-1401 (2011).
138. Daito H, Kikuchi T, Sakakibara T, Gomi K, Damayanti T, Zaini J, Tode N, Kanehira M, Koyama S, Fujimura S, Ebina M, Ishii KJ, Akira S, Takai T, Watanabe A, Nukiwa T. Mycobacterial hypersensitivity pneumonitis requires TLR9-MyD88 in lung CD11b+ CD11c+ cells. Eur. Respir J. 38: 688-701 (2011).
137. Nakamura, Y., Fujita, Y., Ueno, M., Takai, T. and Yamashita, T. Paired immunoglobulin-like receptor B knockout does not enhance axonal regeneration or locomotor recovery after spinal cord injury. J. Biol. Chem. 286: 1876-1883 (2010).
136. Takai T, Nakamura A, Endo S. Role of PIR-B in Autoimmune Glomerulonephritis. J. Biomed. Biotech. 2011: 275302 (2011).
136. Omoto S, Ueno M, Mochio S, Takai T, Yamashita T. Genetic deletion of paired immunoglobulin-like receptor B does not promote axonal plasticity or functional recovery after traumatic brain injury. J. Neurosci. 30: 13045-13052 (2010).
135. Yamamoto M, Kobayashi K, Ishikawa Y, Nakata K, Funada Y, Kotani Y, Masuda A, Takai T, Azuma T, Yoshida M, Nishimura Y. The inhibitory effects of intravenous administration of rabbit IgG on airway inflammation are dependent on Fcgamma receptor IIb on CD11c+ dendritic cells in murine model. Clin. Exp. Immunol. 162: 315-324 (2010).
134. Enomoto Y, Yamanishi Y, Izawa K, Kaitani A, Takahashi M, Maehara A, Oki T, Takamatsu R, Kajikawa M, Takai T, Kitamura T, Kitaura J. Characterization of leukocyte mono-immunoglobulin-like receptor 7 (LMIR7)/CLM-3 as an activating receptor: its similarities to and differences from LMIR4/CLM-5. J. Biol. Chem. 285: 35274-35283 (2010).
133. Yamanishi Y, Kitaura J, Izawa K, Kaitani A, Komeno Y, Nakamura M, Yamazaki S, Enomoto Y, Oki T, Akiba H, Abe T, Komori T, Morikawa Y, Kiyonari H, Takai T, Okumura K, Kitamura T. TIM1 is an endogenous ligand for LMIR5/CD300b: LMIR5 deficiency ameliorates mouse kidney ischemia/reperfusion injury. J. Exp. Med. 207: 1501-1511 (2010).
132. Takai T, Karasuyama H. The study of allergy by Japanese researchers: a historical perspective. Int. Immunol. 12: 1311-1316 (2009).
131. Kubo T, Uchida Y, Watanabe Y, Abe M, Nakamura A, Ono M, Akira S, Takai T. Augmented TLR9-induced Btk activation in PIR-B-deficient B-1 cells provokes excessive autoantibody production and autoimmunity. J. Exp. Med. 206: 1971–1982 (2009).
130. Imada M, Masuda M, Satoh R, Ito Y, Goto Y, Matsuoka T, Endo S, Nakamura A, Kawamoto H, Takai T: Ectopically expressed PIR-B on T cells constitutively binds to MHC class I and attenuates T helper type 1 responses. Int. Immunol. 21:1151-1161 (2009).
129. Otero K, Turnbull IR, Poliani L, Vermi W, Aoshi T, Takai T, Stanley SL, Miller M, Colonna M. MCSF induces macrophage proliferatin and survival through a DAP12-β-catenin signaling pathway. Nat. Immunol. 10: 734–743 (2009).
128. Tassi I, Le Friec G, Gilfillan S, Takai T, Yokoyama WM, Colonna M. DAP10 associates with Ly49 receptors but contributes minimally to their expression and function in vivo. Eur. J. Immunol. 39:1129–1135 (2009).
127. Orr MT, Sun JC, Arase H, Phillips JH, Takai T, Lanier LL. DAP12-independent Ly49H-mediated NK cell responses against mouse cytomegalovirus. J. Exp. Med. 206: 807–817 (2009)
126. Li L, Kaifu T, Obinata M, Takai T: Peroxiredoxin III-deficiency Sensitizes Macrophages to Oxidative Stress. J. Biochem. 145: 425–427 (2009).
125. Inui M, Kikuchi Y, Aoki N, Endo S, Maeda T, Sugahara-Tobinai A, Nakamura A, Kumanogoh A, Colonna M, Takai T. Signal adaptor DAP10 associates with MDL-1 and triggers osteoclastogenesis in cooperation with DAP12. Proc. Nat.l Acad. Sci. USA. 106: 4816−4821 (2009).
124. Helming L, Tomasello E, Kyriakides TR, Martinez FO, Takai T, Gordon S, Vivier E. Essential role of DAP12 signaling in macrophage programming into a fusion-competent state. Sci. Signal. 1: ra11 (2008).
123. Hida S, Yamasaki S, Sakamoto Y, Takamoto M, Obata K, Takai T, Karasuyama H, Sugane K, Saito T, Taki S. Fc receptor γ -chain, a constitutive component of the interleukin-3 receptor, is required for interleukin 3-induced interleukin 4 production in basophils. Nat. Immunol. 10: 214–222 (2009).
122. Endo S, Sakamoto Y, Nakamura A, Takai T. Regulation of cytotoxic T lymphocyte triggering by PIR-B on dendritic cells. Proc. Natl. Acad. Sci. USA. 105: 14515−14520 (2008).
121. Mori Y, Tsuji S, Inui M, Sakamoto Y, Endo S, Ito Y, Fujimura S, Koga T, Nakamura A, Takayanagi H, Itoi E, Takai T. Inhibitory immunoglobulin-like receptors LILRB and PIR-B negatively regulate osteoclast development. J. Immunol. 181: 4742−4751 (2008).
120. Torii I, Oka S, Hotomi M, Benjamin WH Jr, Takai T, Kearney JF, Briles DE, Kubagawa H. PIR-B-deficient mice are susceptible to Salmonella infection. J. Immunol. 181: 4229−4239 (2008).
119. Kasai S, Inui M, Nakamura K, Kakizaki Y, Endo S, Nakamura A, Ito S, Takai T. A novel regulatory role of gp49B on dendritic cells in T cell priming. Eur. J. Immunol. 38: 2426−2437 (2008).
118. Kofu K, Yamabe E, Matsuzawa A, Onda D, Suemizu H, Sasaki E, Tanioka Y, Yagita H, Suzuki D, Kametani Y, Takai T, Toyoda A, Habu S, Satake M. Comparison of 30 immunity-related genes from thecommon marmoset with orthologues from human and mouse. Tohoku J. Exp. Med. 215: 167−180 (2008).
117. Masuda A, Yoshida M, Shiomi H, Ikezawa S, Takagawa T, Tanaka H, Chinzei R, Ishida T, Morita Y, Kutsumi H, Inokuchi H, Wang S, Kobayashi K, Mizuno S, Nakamura A, Takai T, Blumberg RS, Azuma T. Fcγ Receptor Regulation of Citrobacter rodentium Infection. Infect. Immunity 76: 1728−1737 (2008).
116. Shinohara M, Koga T, Okamoto K, Sakaguchi S, Arai K, Yasuda H, Takai T, Kodama T, Morio T, Geha RS, Kitamura D, Kurosaki T, Ellmeier W, Takayanagi H. Tyrosine kinases Btk and Tec regulate osteoclast differentiation by linking RANK and ITAM signals. Cell 132: 794-806 (2008).
115. Yamanishi Y, Kitaura J, Izawa K, Matsuoka T, Oki T, Lu Y, Shibata F, Yamazaki S, Kumagai H, Nakajima H, Maeda-Yamamoto M, Tybulewicz VLJ, Takai T, Kitamura T. Analysis of mouse LMIR5/CLM7 as an activating receptor: differential regulation of LMIR5/CLM7 in ouse versus human cells. Blood 111: 688−698 (2008).
114. Giurisato E, Cella M, Takai T, Kurosaki T, Feng Y, Longmore GD, Colonna M, Shaw AS. PI3-kinase activation is required to form the NKG2D immunological synapse. Mol. Cell. Biol. 27: 8583−8599 (2007).
113. Kojima T, Obata K, Muikai K, Sato S, Takai T, Minegishi Y, Karasuyama H. A CD200 receptor-like protein CD200R3 functions as an activating receptor expressed exclusively on basophils and mast cells. J. Immunol. 179: 7093−7100 (2007).
112. Divangahi M, Yang T, Kugathasan K, McCormick S, Takenaka S, Gaschler G, Ashkar A, StampfliM, Gauldie J, Bramson J, Takai T, Brown E, Yokoyama WM, Aoki N and Xing Z.Critical Negative Regulation of type 1 T cell immunity and immunopathology by signaling adaptor DAP12 during intracellular infection. J. Immunol. 179: 4015−4026 (2007).
111. Inoue Y, Kaifu T, Sugahara−Tobinai A, Nakamura A, Miyazaki J-I, Takai T. Activating Fcγ receptors participate in the development of autoimmune diabetes in NOD mice. J. Immunol. 179: 764−774 (2007).
110. Ochi S, Shinohara M, Sato K, Gober H-J, Koga T, Kodama T, Takai T, Miyasaka N, Takayanagi H. Pathological role of osteoclast costimulation in arthritis-induced bone loss. Proc. Natl. Acad. Sci. USA 104: 11394−11399 (2007).
109. Hara H, Ishihara C, Takeuchi A, Xue L, Morris SW, Imanishi T, Inui M, Takai T, Shibuya A, Koseki H, Yoshida H, Penninger JM, Saito T. The adaptor protein CARD9 is essential for the activation of myeloid cells through ITAM-associated and Toll-like receptors. Nat. Immunol. 8: 619−629 (2007).
108. Masuda A*, Nakamura A* (*equal contributor), Maeda T, Sakamoto Y, Takai, T. Cis binding between inhibitory receptors and MHC class I can regulate mast cell activation. J. Exp. Med. 204: 907−920 (2007).
107. Izawa K, Kitaura J, Yamanishi Y, Matsuoka T, Oki T, Shibata F, Kumagai H, Nakajima H, Maeda-Yamamoto M, Hauchins JP, Tybulewicz VL, Takai T, Kitamura T. Functional analysis of an activating receptor LMIR4 as a counterpart of an inhibitory receptor LMIR3. J. Biol. Chem. 282: 17997−18008 (2007).
106. Li L, Shoji W, Takano H, Nishimura N, Aoki Y, Takahashi R, Goto S, Kaifu T, Takai T, Obinata M. Increased susceptibility of MER5 (peroxiredoxin III) knockout mice to LPS-induced oxidative stress. Biochem. Biophys. Res. Commun. 355: 715−721 (2007).
105. Nakayama M, Underhill DM, Petersen TW, Li B, Kitamura T, Takai T, Aderem A. Paired Ig-like receptors bind to bacteria and shape TLR-mediated cytokine production. J. Immunol. 178: 4250−4259 (2007).
104. Nakahashi C, Tahara-Hanaoka S, Totsuka N, Okoshi Y, Takai T, Ohkochi N, Honda S-i, Shibuya K, Shibuya A. Dual assemblies of an activating immune receptor, MAIR-II, with ITAM-bearing adaptors DAP12 and FcRγ chain on peritoneal macrophages. J. Immunol. 178: 765−770 (2007).
103. Sato K, Suematsu A, Nakashima T, Takemoto-Kimura S, Aoki K, Morishita Y, Asahara H, Ohya K, Yamaguchi A, Takai T, Kodama T, Chatila TA, Bito H, Takayanagi H. Regulation of osteoclast differentiation and function by the CaMK/CREB pathway. Nat. Med. 12:1410−1416 (2007).
102. Kitamura K*, Takeda K*, Koya T*, Miyahara N* (*equal contributors), Kodama T, Dakhama A, Takai T, Hirano A, Tanimoto M, Harada M, Gelfand EW. Critical role of the Fc receptor γ-chain on APCs in the development of allergen-induced airway hyperresponsiveness and inflammation. J. Immunol. 178: 480−488 (2007).
101. Iizuka S, Kaifu T, Nakamura A, Obinata M, Takai T. Establishment and functional characterization of novel natural killer cell lines derived from a temperature-sensitive SV40 large T antigen transgenic mouse. J. Biochem. (Tokyo) 140: 255−265 (2006).
100. Kanehira M, Kaifu T, Maya K, Kaji M, Nakamura A, Obinata M, Takai T. Novel mast cell lines with enhanced proliferative and degranulative abilities established from temperature-sensitive SV40 large T antigen transgenic mice. J. Biochem. (Tokyo) 140: 211−220 (2006).
99. Takegahara N, Takamatsu H, Toyofuku T, Tsujimura T, Okuno T, Yukawa K, Mizui M, Yamamoto M, Prasad DV, Suzuki K, Ishii M, Terai K, Moriya M, Nakatsuji Y, Sakoda S, Sato S, Akira S, Takeda K, Inui M, Takai T, Ikawa M, Okabe M, Kumanogoh A, Kikutani H. Plexin-A1 and its interaction with DAP12 in immune responses and bone homeostasis. Nat. Cell Biol. 8: 615−622 (2006).
98. Graham DB, Cella M, Giurisato E, Fujikawa K, Miletic AV, Kloeppel T, Brim K, Takai T, Shaw AS, Colonna M, Swat W. Vav1 controls DAP10-mediated natural cytotoxicity by regulating actin and microtubule dynamics. J. Immunol. 177: 2349−2355 (2006).
97. Blasius AL, Cella M, Maldonado J, Takai T, Colonna M. Siglec-H is an IPC-specific receptor that modulates type I IFN secretion through DAP12. Blood 107: 2474−2476 (2006).
96. Okazaki T, Otaka Y, Wang J, Hiai H, Takai T, Ravetch JV, Honjo T. Hydronephrosis associated with anti-urothelial and anti-nuclear autoantibodies in BALB/c-Fcgr2b-/-Pdcd1-/-mice. J. Exp. Med. 202: 1643−1648 (2005).
95. Turnbull IR, McDunn JE, Takai T, Townsend RR, Cobb JP, Colonna M. DAP12 (KARAP) amplifies inflammation and increases mortality from endotoxemia and septic peritonitis. J. Exp. Med. 202: 363−369 (2005).
94. Xie X, He H, Colonna M, Seya T, Takai T, Croy BA. Pathways participating in activation of mouse uterine natural killer cells during pregnancy. Biol. Reprod. 73: 510−518 (2005).
93. Zhang H, Meng F, Chu C-L, Takai T, Lowell C. The src-family kinases Hck and Fgr negatively regulate neutrophil and dendritic cell chemokine signaling via PIR-B. Immunity 22: 235−246 (2005).
92. Ebihara, S., Endo, S., Ito, K., Ito, Y., Akiyama, K., Obinata, M., Takai, T. Immortalized dendritic cell line with efficient antigen-presenting ability established from transgenic mice harboring temperature-sensitive SV40 large T-antigen gene. J. Biochem. (Tokyo) 136: 321−328 (2004).
91. Pereira S, Zhang H, Takai T, Lowell CA. The inhibitory receptor PIR-B negatively regulates neutrophil and macrophage integrin signaling. J. Immunol. 173: 5757−5765 (2004).
90. Nakamura A, Kobayashi E, Takai T. Exacerbated graft-versus-host disease in Pirb-/- mice. Nat. Immunol. 5: 623−629 (2004).
89. Koga T*, Inui M*, Inoue K, Kim S, Suematsu A, Kobayashi E, Iwata T, Ohnishi H, Matozaki T, Kodama T, Taniguchi T, Takayanagi H, Takai T. (*equal contributor) Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. Nature 428, 758–763 (2004).
88. Yamaguchi, A., Katsuyama, K., Nagahama, K., Takai, T., Aoki, I., Yamanaka, S. Possible role of autoantibody in the pathophysiology of GM2 angliosidoses. J. Clin. Invest. 113: 200–208 (2004).
87. Takai, T. Role of paired immunoglobulin-like receptor (PIR)-B in humoral immune response. Allergol. Int. 2: 93–99 (2004).
86. Nakamura, A., Takai , T. A role of FcγRIIB in the development of collagen-induced arthritis. Review. Biomed. Pharmacother. 5: 623–629 (2004).
85. Watanabe, T., Okano, M., Hattori, H., Yoshino, T., Ohno, N., Ohta, N., Sugata, Y., Orita, Y., Takai, T., Nishizaki, K. Roles of FcγRIIB in nasal eosinophilia and IgE production in murine allergic rhinitis. Am. J. Respir. Crit. Care Med. 169: 105–112 (2004).
84. Yada, A., Ebihara, S., Matsumura, K., Akiyama, K., Aiba, S., and Takai, T. Contribution of Fcγ receptors to antigen presentation and elicitation of humoral response in vivo. Cell. Immunol. 225: 21–32 (2003).
83. Nakahara, J., Tan-Takeuchi, K., Seiwa, C, Gotoh, M., Kaifu, T., Ujike, A., Inui, M., Yagi, T., Aiso, S., Takai, T., and Asou, H. Signaling via immunoglobulin Fc receptors induces oligodendrocyte precursor cell differentiation. Dev. Cell 4: 841–852 (2003).
82. Takai, T., Nakamura, A., Akiyama, K. Fc receptors as potential targets for treatment of allergy, autoimmune disease and cancer. Curr. Drug Targets Immune Endocr. Metabol. Disorders. 3: 187–197 (2003).
81. Nakamura, A., Nukiwa, T., Takai, T. Deregulation of peripheral B cell development in enhanced severity of collagen-induced arthritis in Fc γRIIB-deficient mice. J. Autoimmu. 20: 227–236 (2003).
80. Nakamura, A., Mori, Y., Hagiwara, K., Suzuki, T., Sakakibara, T., Kikuchi, T., Igarashi, T., Ebina, M., Miyazaki, J., Takai, T., Nukiwa, T. Increased susceptibility to LPS-induced endotoxin shock in secretory leukoprotease inhibitor (SLPI)-deficient mice. J. Exp. Med. 197: 669–674 (2003).
79. Yajima K, Nakamura A, Sugahara A, Takai T. FcγRIIB deficiency with Fas mutation is sufficient for the development of systemic autoimmune disease. Eur. J. Immunol. 33: 1020–1029 (2003).
78. Taube C, Takeda K, Dakhama A, Rha Y, Joetham A, Park J.-W, Ballhorn A, Takai T, Benchich KR, Nick JA, Gelfand EW. Transient neutrophil inflammation after allergen challenge is dependent on specific antibodies and Fc receptors. J. Immunol. 170: 4301–4309 (2003).
77. Nieswandt, B., Bergmeier, W., Schulte, V., Takai, T., Baumann, U., Schmidt, R.E., Zirngibl, H., Bloch, W. and Gessner, J.E. Targeting of platelet integrin αIIbβ3 determines systemic reaction and bleeding in murine thrombocytopenia regulated by activating and inhibitory FcγRs. Int. Immunol. 15: 341–349 (2003).
76. Akiyama K, Ebihara S, Yada, A., Matsumura, K., Aiba, S., Nukiwa, T., and Takai T. Targeting of apoptotic tumor cells to Fcγ receptors provides efficient and versatile vaccination against tumors by dendritic cells. J. Immunol. 170: 1641–1648 (2003).
75. Kaifu, T., Nakahara, J., Inui, M., Mishima, K., Momiyama, T., Kaji, M., Sugahara, A., Koito, H., Ujike-Asai, A., Nakamura, A., Kanazawa, K., Tan-Takeuchi, K., Iwasaki, K., Yokoyama, W.M., Kudo, A., Fujiwara, M., Asou, H., and Takai, T. Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice. J. Clin. Invest. 111: 323–332 (2003).
74. Takai T. Roles of Fc receptors in autoimmunity. Nat. Rev. Immunol. 2: 580–592 (2002).
73. Ujike A, Takeda K, Nakamura A, Ebihara S, Akiyama K, Takai T. Impaired dendritic cell maturation and increased TH2 responses in PIR-B-/- mice. Nat. Immunol. 3: 542–548 (2002).
72. Makabe-Kobayashi Y, Hori Y, Adachi T, Ishigaki-Suzuki S, Kikuchi Y, Kagaya Y, Shirato K, Nagy A, Ujike A, Takai T, Watanabe T, and Ohtsu H. The control effect of histamine on the body temperature and respiratory function in IgE-dependent systemic anaphylaxis. J. Allergy Clin. Immunol. 110, 298–303 (2002).
71. Kato I, Takai T, and Kudo A. The pre-B cell receptor signaling for apoptosis is negatively regulated by FcγRIIB. J. Immunol 168: 629-634 (2002).
70. Kubo, S., Matsuoka, K., Taya, C., Kitamura, F., Takai, T., Yonekawa, H., Karasuyama, H. Drastic up-regulation of FcεRI on mast cells is induced by IgE binding through stabilization and accumulation of FcμRI on the cell surface. J. Immunol. 167: 3427–3434 (2001).
69. Takai, T., and Ono, M. Activating and inhibitory nature of the murine paired Ig-like receptor (PIR) family. Immun. Rev. 181: 215–222 (2001).
68. Yuasa, T., Ono, M., Watanabe, T., and Takai, T. Lyn is essential for Fcγ receptor III-mediated systemic anaphylaxis but not for the Arthus reaction. J. Exp. Med. 193: 563–572 (2001).
67. Kaji, K., Takeshita, S., Miyake, K., Takai, T., and Kudo, A. Functional association of CD9 molecule with FcγIII receptor in macrophages. J. Immunol. 166: 3256–3265 (2001).
66. Yoneto, T., Waki, S., Takai, T., Tagawa, Y., Iwakura, Y., Mizuguchi, J., Nariuchi, H., and Yoshimoto, T. A critical role of Fc receptor-mediated antibody-dependent phagocytosis in the host resistance to blood- stage plasmodium berghei XAT infection. J. Immunol. 166: 6236–6241 (2001).
65. Lee, K.H., Ono, M., Inui, M., Yuasa, T., and Takai, T. Stimulatory function of gp49A, a murine Ig-like receptor, in RBL-2H3 cells. J. Immunol. 165: 4970–4977 (2000).
64. Onah DN, Uchiyama F, Nagakui Y, Ono M, Takai T, Nawa Y. Mucosal defence against gastrointestinal nematodes: Responses of mucosal mast cells and mouse mast cell protease 1 during primary Strongyloides venezuelensis infection in FcRγ-knockout mice. Infect. Immun. 68: 4968–4971 (2000).
63. Wakayama, H., Hasegawa, Y., Kawabe, T., Hara, T., Matsuo, S., Mizuno, M., Takai,T., Kikutani, H., Shimokata, K. Abolition of anti-glomerular basement membrane antibody-mediated glomerulonephritis in FcRγ-deficient mice. Eur. J. Immunol. 30: 1182–1190 (2000).
62. Schiller, C., Janssen-Graalfs, I., Baumann, U., Schwerter-Strumpf, K., Izui, S., Takai, T., Schmidt, R.E., and Gessner, J.E. Mouse FcgRII is a negative regulator of FcγRIII in IgG immune complex triggered inflammation but not in autoantibody induced hemolysis. Eur. J. Immunol. 30:481–490 (2000).
61. Nakamura, A., Yuasa, T., Ujike, A., Ono, M., Nukiwa, T., Ravetch, J.V., Takai, T. Fcγ receptor IIB-deficient mice develop Goodpasture's syndrome upon immunization with type IV collagen: A novel murine model for autoimmune glomerular basement membrane disease. J. Exp. Med. 191: 899–906 (2000).
60. Cortegano, I., del Pozo, V., C?daba, B., Arrieta, I., Gallardo, S., Rojo, M., Aceituno, E., Takai, T., Verbeek, S., Palomino, P., Liu, F.-T., and Lahoz, C. Interaction between galectin-3 and FcγRII induces down-regulation of IL-5 gene: Implication of the promoter sequence IL-5REIII. Glycobiol. 10: 237–242 (2000).

1999年以前の論文:計59報(省略)

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