2006 Fiscal Year Final Research Report Summary
Acquisition of Signal Information for Immune Surveillance and Determination of Immune Responses
| Project/Area Number |
15078201
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | RIKEN (2004-2006)
Chiba University (2003) |
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Principal Investigator |
SAITO Takashi RIKEN, Laboratory for Cell Singaling, Group Director, 免疫シグナル研究グループ, グループディレクター (50205655)
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| Project Period (FY) |
2003 – 2006
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| Keywords | Immunology / signal transduction / T cell / immunological synapse / NFκB / IRAK-4 / ADAP |
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| Research Abstract |
We aimed to clarify the mechanism on the acquisition of the information of immune recognition and regulation of immune responses. As the central mechanism of immune surveillance, dendritic cells (DC) first recognize pathogens upon infection, and then innate immunity is activated, which in turn induces antigen-specific recognition and activation of T cells. In this project, we have clarified that IRAK-4, a central regulatory serin/threonine kinase in innate immune signaling, plays also a critical role in T cell activation as the central response in the adaptive immunity. In IRAK-4-deficient mice, proliferation and cytotoxic function of CD8+ T cells were impaired upon LCMV infection. We analyzed whether the impaired response was attributed to the defects in innate response by DCs or T cells by using T cell transfer experiments, and found that T cell activation was impaired in both MHC class I and II-restricted responses. Indeed, we found that not only in vivo T cell responses but also in vitro responses including allogenic responses, super-antigen responses, and responses upon anti-TCR stimulation. By analyzing the defective signaling pathways, particularly NF-AT or NF-κB activation pathways, we found that NF-κB activation was suppressed and impaired phosphorylation of PKCθ appeared to be responsible for the defective NF-κB activation. These results indicate that IRAK-4 plays a critical role in TCR activation signals by directing towards NF-κB activation. We further analyzed the mechanism of IRAK-4-mediated NF-κB specific activation, and found that IRAK-4 associates with ZAP-70 in the over-expression system. IRAK-4 appears to be recruited together with ZAP-70 to the vicinity of TCR upon stimulation, and is involved in activation regulation. Our result that IRAK-4 is important for NF-KB activation in both innate and acquired immunities suggests that NF-κB activation by IRAK-4 has been conserved through phylogenic development.
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Research Products
(63 results)
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[Journal Article] Mechanistic basis of pre-T cell receptor-mediated autonomous signaling critical for thymocyte development.2006
Author(s)
Yamasaki, S.Ishikawa, E., Sakuma, M., Ogata, K., Sakata-Sogawa, K., Hiroshima, M., Wiest, D.L., Tokunaga, M., Saito, T.
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Journal Title
Nat Immunol. 7(1)
Pages: 67-75
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] A critical role for the innate immune signaling molecule IRAK-4 in T cell activation.2006
Author(s)
Suzuki, N., Suzuki, S., Millar, D.G., Unno, M., Hara, H., Calzascia, T., Yamasaki, S., Yokosuka, T., Chen, N-J., Elford, A.R., Suzuki, J-I., Takeuchi, A., Mirtsos, C., Bouchard, D., Ohashi, P.S., Yeh, W-C., Saito, T.
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Journal Title
Science 311
Pages: 19271932
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] In vivo overexpression of CTLA-4 suppresses lymphoproliferative diseases and thymic negative selection.2005
Author(s)
Takahashi, S., Kataoka, H., Hara, S., Yokosuka, T., Takase, K., Yamasaki, S., Kobayashi, W., Saito, Y., Saito, T.
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Journal Title
Eur. J. Immunol. 35
Pages: 399-407
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] CD25+CD4+ regulatory T cells exert in vitro suppressive activity independently of CTLA-4.2005
Author(s)
Kataoka, H., Takahashi, S., Takase, K, Yamasaki, S., Yokosuka, T., Koike, T., Saito, T
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Journal Title
Int. Immunol. 17(4)
Pages: 421-427
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Heterotypic interaction of CRTAM with Nec12 induces cell adhesion on activated NK cells and CD8+ T cells.2005
Author(s)
Arase, N., Takeuchi, A., Unno, M., Hirano, S., Yokosuka, T., Arase, H., Saito, T.
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Journal Title
Int. Immunol. 17(9)
Pages: 1227-1237
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Newly generated T cell receptor microclusters initiate and sustain T cell activation by recruitment of Zap 70 and SLP-76.2005
Author(s)
Yokosuka, T.Sakata-Sogawa, K., Kobayashi, W., Hiroshima, M., Hashimoto-Tane, A., Tokunaga, M., Dustin, M.L., Saito, T.
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Journal Title
Nat Immunol. 6(12)
Pages: 1253-1262
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] FcERIyimmunoreceptor tyrosine-based activation motif is differentially required for mast cell function in vivo.2004
Author(s)
Sakurai, D., Yamasaki, S., Arase, K., Park, S.Y., Arase, H., Konno, A., Saito, T.
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Journal Title
J. Immunol. 172(4)
Pages: 2374-2381
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Overexpression of human acyl CoA thioesterase upregulates2004
Author(s)
Ishizuka, M., Toyama, Y., Watanabe, H., Fujiki, Y., Takeuchi, A., Yamasaki, S., Yuasa, S., Miyazaki, M., Nakajima, N., Taki, S., Saito, T.
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Journal Title
Exp. Cell. Res. 297(1)
Pages: 127-141
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] NFAM1, a new ITAM+ surface molecule that regulates development and signaling of B lymphocytes.2004
Author(s)
Ohtsuka, M., Arase, H., Takeuchi, A., Yamasaki, S., Shiina, R., Suenaga, T., Sakurai, D., Yokosuka, T., Arase, N., Iwashima, M., Kitamura, T., Moriya, H., Saito, T.
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Journal Title
Proc. Natl. Acad. Sci. USA 101(21)
Pages: 8126-8131
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Involvement of FcRy in signal transduction of osteoclast-associated receptor (OSCAR).2004
Author(s)
Ishikawa, S., Arase, N., Suenaga, T., Saita, Y., Noda, M., Kuriyama, T., Arase, H., Saito, T
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Journal Title
Int. Immunol. 16(7)
Pages: 1019-1025
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] The molecular adapter Carmal controls entry of IKK into the central immune synapse.2004
Author(s)
Hara, H., Bakal, C, Wada, T., Bouchard, D., Rottapel, R., Saito, T., Penninger, J.M.
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Journal Title
J. Exp. Med. 200(9)
Pages: 1167-1177
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Predominant role of FcyRIII in the induction of accelerated nephrotoxic glomerulonephritis.2003
Author(s)
Fujii, T., Hamano, Y., Ueda, S., Akikusa, B., Yamasaki, S., Ogawa, M., Saisho, H., Verbeek, J.S., Taki, S., Saito, IV
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Journal Title
Kidney Intl. 64
Pages: 1406-1416
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] IL-1R-associated kinase 4 is required for lipopolysaccharide-induced activation of APC.2003
Author(s)
Suzuki, N., Suzuki, S., Eriksson, U., Hara, H., Mirtosis, C., Chen, N-J., Wada, T., Bouchard, D, Hwang, I., Takeda, K., Fujita, F., Der, S., Penninger, J.M., Akira, A., Saito, T., Yeh, W-C.
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Journal Title
J. Immunol. 171
Pages: 6065-6071
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Reduction of glycosphingolipid levels in lipid rafts affects the expression state and function of glycosylphosphatidylinositol-anchored proteins but does not impair signal transduction via the T cell receptor.2003
Author(s)
Nagafuku, M, Kabayama, K, Oka, D., Kato, A., Tani-ichi, S Shimada, Y., Ohno-Iwashita, Y., Yamasaki, S., Saito, T., Iwabuchi, K., Hamaoka, T., Inokuchi, J., Kosugi, A
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Journal Title
J.Biol.Chem. 278(51)
Pages: 51920-51927
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Diverging signaling events control the pathway of GPVI downregulation in vivo.
Author(s)
Rabie, T., Varga-Szabo, D., Bender, M., Pozgaj, R., Lanza, F., Saito, T., Watson, S.P., Nieswandt, B.
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Journal Title
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] TLR2 directly triggers Thl effector functions.
Author(s)
Imanishi, T., Hara, H., Suzuki, S., Suzuki, N., Akira, S., Saito, T.
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Journal Title
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Card9 is essential for activation of myeloid cells through ITAM-associated receptors and Toll-like receptors.
Author(s)
Hara, H., Ishihara, C., Takeuchi, A., Imanishi, T., Xue, L., Morris, S., Inui, M., Takai, T., Shibuya, A., Saijo, S., Iwakura, Y., Ohno, N., Penninger, J.M., Koseki, H., Yoshida, H., Saito, T.
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Journal Title
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] LAT and NTAL mediate IgE-induced sustained Erk activation critical for mast cell survival.
Author(s)
Yamasaki, S., Ishikawa, E., Sakuma, M., Kanagawa, 0., Cheng, A.M., Malissen, B., Saito, T.
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Journal Title
Mol. Cell. Biol. (in press)
Description
「研究成果報告書概要(欧文)」より
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