IMMUNE REGULATION BY IMMUNOGLOBULIN-LIKE RECEPTORS

• Project/Area Number: 14207014
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Immunology
• Research Institution: Tohoku University
• Principal Investigator: TAKAI Toshiyuki TOHOKU UNIVERSITY INSTITUTE OF DEVELOPMENT, AGING AND CANCER, PROFESSOR, 加齢医学研究所, 教授 (20187917)
• Co-Investigator(Kenkyū-buntansha): 海部 知則 東北大学, 加齢医学研究所, 助手 (90343037) ; 中村 晃 東北大学, 加齢医学研究所, 助手 (20344723)
• Project Period (FY): 2002 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥29,770,000 (Direct Cost: ¥22,900,000、Indirect Cost: ¥6,870,000); Fiscal Year 2004: ¥9,490,000 (Direct Cost: ¥7,300,000、Indirect Cost: ¥2,190,000); Fiscal Year 2003: ¥9,360,000 (Direct Cost: ¥7,200,000、Indirect Cost: ¥2,160,000); Fiscal Year 2002: ¥10,920,000 (Direct Cost: ¥8,400,000、Indirect Cost: ¥2,520,000)
• Keywords: Ig-like receptor / PIR / allergy / autoimmunity / transplantation / GVHD / immunoregulation / PIR-B / Th2 response / dendritic cell / MHC class I / IgLR / Allergy / gene targeting

Research Abstract

PIRs expressed on B and myeloid cells form a unique 'self' recognition. Activating PIR-A and inhibitory PIR-B were shown to bind various murine MHC class I (H-2) molecules. In vitro H-2 tetramer stimulation of PIRs induced intracellular phosphotyrosine signaling. PIR-B-deficient mice transferred with allogeneic splenocytes showed exacerbated graft-versus-host disease, which was due to the augmented activation of the recipient's dendritic cells (DCs) with the concomitant up-regulation of PIR-A and increased IFN-production. PIR-A-induced DC activation also led to increased proliferation of donor cytotoxic T cells. Thus, PIR-A and PIR-B are counter-acting receptors that play key roles for successful tissue transplantation, and may regulate irrelevant reaction to autologous tissues in a constitutive fashion under physiological circumstances.
To analyze the etiology of mild osteopetrosis in DAP12 (DNAX protein 12)-deficient mice, we examined the bone morphology in FcRγ-deficient (FcRγ--) mice and DAP12/FcRγ double deficient (DKO) mice. Histological examination revealed that FcRγ--mice did not show any remarkable osteopetrosis. However, we found that DKO mice exhibited much more severe osteopetrosis than DAP12--mice, suggesting that either DAP12 or FcRγ is required for normal bone remodeling. In osteoclast precursor cells, FcRγ and DAP12 associate with multiple IgLRs including OSCAR and PIR-A ; and TREM-2 and SIRPβ1, respectively, and activate Ca^2 signal through PLCγ. Thus, ITAM-dependent costimulatory signals activated by multiple IgLRs are indispensable for the maintenance of bone homeostasis, indicating that RANK and M-CSF receptor are not sufficient to activate signals required for osteoclastogenesis.

Research Products

• [Journal Article] The inhibitory receptor PIR-B negatively regulates neutrophil and macrophage integrin signaling. (2004)
  • Author(s): Pereira S, Zhang H, Takai T, Lowell CA.
  • Journal Title: J.Immunol. 173(9) Pages: 5757-5765
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Immortalized dendritic cell line with efficient cross-priming ability established from transgenic mice harboring the temperature-sensitive SV40 large T-antigen gene. (2004)
  • Author(s): Ebihara S, Endo S, Ito K, Ito Y, Akiyama K, Obinata M, Takai T.
  • Journal Title: J.Biochem. 136 Pages: 321-328
  • NAID: 10016202020
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Exacerbated graft-versus-host disease in Pirb-/- mice. (2004)
  • Author(s): Nakamura A, Kobayashi E, Takai T.
  • Journal Title: Nature Immunol. 5(6) Pages: 623-629
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. (2004)
  • Author(s): Koga T, et al.
  • Journal Title: Nature 428 Pages: 758-763
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Possible role of autoantibody in the pathophysiology of GM2 angliosidoses. (2004)
  • Author(s): Yamaguchi, A., Katsuyama, K., Nagahama, K., Takai, T., Aoki, I., Yamanaka, S.
  • Journal Title: J.Clin.Invest. 113 Pages: 200-208
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Roles of FcγRIIB in nasal eosinophilia and IgE production in murine allergic rhinitis. (2004)
  • Author(s): Watanabe, T.et al.
  • Journal Title: Am.J.Respir.Crit.Care Med. 1699 Pages: 105-112
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Exacerbated graft-versus-host disease in Pirb-/-mice. (2004)
  • Author(s): Nakamura A, Kobayashi E, Takai T.
  • Journal Title: Nature Immunol. (Published online : 16 May 2004) 5(6) Pages: 623-629
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. (2004)
  • Author(s): 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)
  • Journal Title: Nature 428 Pages: 758-763
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Roles of Fcγ RIIB in nasal eosinophilia and IgE production in murine allergic rhinitis. (2004)
  • Author(s): Watanabe, T., Okano, M., Hattori, H., Yoshino, T., Ohno, N., Ohta, N., Sugata, Y., Orita, Y., Takai, T., Nishizaki, K.
  • Journal Title: Am.J.Respir.Crit.Care Med. (Epub ahead of print, Oct.2,2003) 169 Pages: 105-112
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The inhibitory receptor PIR-B negatively regulates neutrophil and macrophage integrin signaling. (2004)
  • Author(s): Pereira S, Zhang H, Takai T, Lowell CA
  • Journal Title: J.Immunol. 173(9) Pages: 5757-5765
• [Journal Article] Immortalized dendritic cell line with efficient cross-priming ability established from transgenic mice harboring the temperature-sensitive SV40 large T-antigen gene. (2004)
  • Author(s): Ebihara S, Endo S, Ito K, Ito Y, Akiyama K, Obinata M, Takai T
  • Journal Title: J.Biochem. 136 Pages: 321-328
  • NAID: 10016202020
• [Journal Article] Exacerbated graft-versus-host disease in Pirb-/- mice. (2004)
  • Author(s): Nakamura A, Kobayashi E, Takai T
  • Journal Title: Nature Immunol. 5(6) Pages: 623-629
• [Journal Article] Roles of FcγRIIB in nasal eosinophilia and IgE production in murine allergic rhinitis. (2004)
  • Author(s): Watanabe, T. et al.
  • Journal Title: Am.J.Respir.Crit.Care Med. 169 Pages: 105-112
• [Journal Article] Contribution of Fcγ receptors to antigen presentation and elicitation of humoral response in vivo. (2003)
  • Author(s): Yada, A., Ebihara, S., Matsumura, K., Akiyama, K., Aiba, S., Takai, T.
  • Journal Title: Cell.Immunol. 225(1) Pages: 21-32
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Signaling via immunoglobulin Fc receptors induces oligodendrocyte precursor cell differentiation. (2003)
  • Author(s): Nakahara, J.et al.
  • Journal Title: Dev.Cell. 4(6) Pages: 841-842
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Deregulation of peripheral B cell development in enhanced severity of collagen-induced arthritis in FcγRIIB-deficient mice. (2003)
  • Author(s): Nakamura, A., Nukiwa, T., Takai, T.
  • Journal Title: J.Autoimmu. 20 Pages: 227-236
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Fc receptors as potential targets for treatment of allergy, autoimmune disease and cancer. (2003)
  • Author(s): Takai, T., Nakamura, A., Akiyama, K.
  • Journal Title: Current Drug Targets-Immune, Endocrine & Metabolic Disorders. 3 Pages: 187-197
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Increased susceptibility to LPS-induced endotoxin shock in secretory leukoprotease inhibitor (SLPI)-deficient mice. (2003)
  • Author(s): Nakamura, A.et al.
  • Journal Title: J.Exp.Med. 197 Pages: 669-674
  • NAID: 120004898439
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] FcgRIIB deficiency with Fas mutation is sufficient for the development of systemic autoimmune disease. (2003)
  • Author(s): Yajima K, Nakamura A, Sugahara A, Takai T.
  • Journal Title: Eur.J.Immunol. 33 Pages: 1020-1029
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Transient neutrophil inflammation after allergen challenge is dependent on specific antibodies and Fc receptors. (2003)
  • Author(s): Taube C, et al.
  • Journal Title: J.Immunol. 170 Pages: 4301-4309
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Targeting of platelet integrin α IIbβ3 determines systemic reaction and bleeding in murine thrombocytopenia regulated by activating and inhibitory FcgRs (2003)
  • Author(s): Nieswandt, B.et al.
  • Journal Title: Int.Immunol. 15 Pages: 341-349
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Targeting of apoptotic tumor cells to Fcγ receptors provides efficient and versatile vaccination against tumors by dendritic cells. (2003)
  • Author(s): Akiyama K, Ebihara S, Yada, A., Matsumura, K., Aiba, S., Nukiwa, T., Takai, T.
  • Journal Title: J.Immunol. 170(4) Pages: 1641-1648
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice. (2003)
  • Author(s): Kaifu, T.^* et al.
  • Journal Title: J.Clin.Invest. 111(3) Pages: 323-332
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Contribution of Fc γ receptors to antigen presentation and elicitation of humeral response in vivo. (2003)
  • Author(s): Yada, A., Ebihara, S., Matsumura, K., Akiyama, K., Aiba, S., Takai, T.
  • Journal Title: Cell.Immunol. 225(1) Pages: 21-32
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Signaling via immunoglobulin Fc receptors induces oligodendrocyte precursor cell differentiation. (2003)
  • Author(s): Nakahara, J., Tan-Takeuchi, K., Seiwa, C, Gotoh, M., Kaifu, T., Ujike, A., Inui, M., Yagi, T., Aiso, S., Takai, T., Asou, H.
  • Journal Title: Dev.Cell 4(6) Pages: 841-852
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Deregulation of peripheral B cell development in enhanced severity of collagen-induced arthritis in Fcγ RIIB-deficient mice. (2003)
  • Author(s): Nakamura, A., Nukiwa, T., Takai, T.
  • Journal Title: J.Autoimmu. 20 Pages: 227-236
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Fc receptors as potential targets for treatment of allergy, autoimmune disease and cancer. (2003)
  • Author(s): Takai, T., Nakamura, A., Akiyama, K.
  • Journal Title: Current Drug Target5-Immune, Endocrine & Metabolic Disorders.(Review) 3 Pages: 187-197
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Increased susceptibility to LPS-induced endotoxin shock in secretory leukoprotease inhibitor (SLPI)-deficient mice. (2003)
  • Author(s): Nakamura, A., Mori, Y., Hagiwara, K., Suzuki, T., Sakakibara, T., Kikuchi, T., Igarashi, T., Ebina, M., Miyazaki, J., Takai, T., Nukiwa, T.
  • Journal Title: J.Exp.Med. 197 Pages: 669-674
  • NAID: 120004898439
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Transient neutrophil inflammation after allergen challenge is dependent on specific antibodies and Fc receptors. (2003)
  • Author(s): Taube C, Takeda K, Dakhama A, Rha Y, Joetham A, Park J.-W, Ballhorn A, Takai T, Benchich KR, Nick JA, Gelfand EW.
  • Journal Title: J.Immunol. 170 Pages: 4301-4309
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Targeting of platelet integrin αIIbβ3 determines systemic reaction and bleeding in murine thrombocytopenia regulated by activating and inhibitory FcgRs (2003)
  • Author(s): Nieswandt, B., Bergmeier, W., Schulte, V., Takai, T., Baumann, U., Schmidt, R.E., Zirngibl, H., Bloch, W, Gessner, J.E.
  • Journal Title: Int.Immunol. 15 Pages: 341-349
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Targeting of apoptotic tumor cells to Fcγ receptors provides efficient and versatile vaccination against tumors by dendritic cells. (2003)
  • Author(s): Akiyama K, Ebihara S, Yada, A., Matsumura, K., Aiba, S., Nukiwa, T., Takai T.
  • Journal Title: J.Immunol. 170(4) Pages: 1641-1648
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice. (2003)
  • Author(s): 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., Takai, T.(*equal contributor)
  • Journal Title: J.Clin.Invest. 111(3) Pages: 323-332
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Roles of Fc receptors in autoimmunity. (2002)
  • Author(s): Takai T.
  • Journal Title: Nature Rev.Immunol. 2 Pages: 580-592
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Impaired dendritic cell maturation and increased TH2 responses in PIR-B-/- mice. (2002)
  • Author(s): Ujike, A., Takeda, K., Nakamura, A., Ebihara, S., Akiyama, K., Takai, T.
  • Journal Title: Nature Immunol. 3 Pages: 542-548
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The control effect of histamine on the body temperature and respiratory function in IgE-dependent systemic anaphylaxis. (2002)
  • Author(s): Makabe-Kobayashi Y, et al.
  • Journal Title: J.Allergy Clin.Immunol. 110 Pages: 298-303
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The pre-B cell receptor signaling for apoptosis is negatively regulated by FcgRIIB. (2002)
  • Author(s): Kato I, Takai T, Kudo A.
  • Journal Title: J.Immunol. 168 Pages: 629-634
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Impaired dendritic cell maturation and increased TH2 responses in PIR-B-/-mice. (2002)
  • Author(s): Ujike, A., Takeda, K., Nakamura, A., Ebihara, S., Akiyama, K., Takai, T.
  • Journal Title: Nature Immunol. 3 Pages: 542-548
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The control effect of histamine on the body temperature and respiratory function in IgE-dependent systemic anaphylaxis. (2002)
  • Author(s): Makabe-Kobayashi Y, Hori Y, Adachi T, Ishigaki-Suzuki S, Kikuchi Y, Kagaya Y, Shirato K, Nagy A, Ujike A, Takai T, Watanabe T, Ohtsu H.
  • Journal Title: J.Allergy Clin.Immunol. 110 Pages: 298-303
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Kaifu T et al.: "Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice"J.Clin.Invest.. 111(3). 323-332 (2003)
• [Publications] Koga T et al.: "ITAM-mediated costimulatory signals cooperate with RANKL for bone homeostasis"Nature. (in press). (2004)
• [Publications] Yamaguchi A et al.: "Possible role of autoantibody in the pathophysiology of GM2 angliosidoses"J.Clin.Invest.. 113(2). 200-208 (2004)
• [Publications] Nakamura A et al.: "Exacerbated graft-versus-host disease in Pirb^<-/-> mice"Nature Immunology. (in press). (2004)
• [Publications] Nakamura, A., et al.: "Deregulation of peripheral B cell development in enhanced severity of collagen-induced arthritis in FcγRIIB-deficient mice"J Autoimmu. (in press). (2003)
• [Publications] Yajima K, et al.: "FcγRIIB deficiency with Fas mutation is sufficient for the development of systemic autoimmune disease"Eur. J. Immunol. 33. 1020-1029 (2003)
• [Publications] Akiyama K, et al.: "Targeting of apoptotic tumor cells to Fcγ receptors provides efficient and versatile vaccination against tumors by dendritic cells"J. Immunol. 170(4). 1641-1648 (2003)
• [Publications] Kaifu, T., et al.: "Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice"J. Clin. Invest. 111(3). 323-332 (2003)
• [Publications] Ujike, A., et al.: "Impaired dendritic cell maturation and increased T_H2 responses in PIR-B^<-/-> mice"Nature Immunol. 3. 542-548 (2002)
• [Publications] Takai T.: "Roles of Fc receptors in autoimmunity."Nature Rev. Immunol. 2. 580-592 (2002)