2005 Fiscal Year Final Research Report Summary
The regulation of innate immune responses by dendritic cells through the interaction with microbes
| Project/Area Number |
14021110
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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 | KEIO UNIVERSITY |
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Principal Investigator |
KOYASU Shigeo Keio University, School of Medicine, Professor, 医学部, 教授 (90153684)
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| Project Period (FY) |
2002 – 2005
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| Keywords | IL-12 / IL-15 / IFN-γ / PI3K / Thl / Listeria / Leishmania / nematode |
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| Research Abstract |
We studied in this program project the role of dendritic cells (DCs) in innate and adaptive immunity against microbes. Upon microbial infection, DCs play an important role in antigen presentation of microbial antigens to T cells. At the same time, DCs stimulated through Toll-like receptor (TLR) produce various cytokines such as interleukin-12 (IL-12) that is crucial for the activation of innate immunity and Thl induction. DCs thus play critical roles in both innate and adaptive immunity. DC-derived IL-12 further induces interferon γ (IFN-γ) from NK cells and DCs. We showed that DC-derived IFN-γ plays an important role in vivo in innate immune response against an intracellular pathogen, Listeria monocytogenes. In addition, we demonstrated that DC-derived IL-15 is critical for the induction of inflammatory responses. The onset of Thl immunity is in part regulated by genetic background. We examined cell types that carry a genetic factor(s) to determine the onset of Thl/Th2 responses by employing Leishmania major infection and found that DCs determine the outcome of Thl/Th2 responses. We also studied signal transduction pathways in DCs and found that the lack of phosphoinositide 3-kinase (PI3K) results in the enhanced IL-12 production by DCs. In contrast, the lack of Pten, a phosphatase that catalyzes a reaction opposite to PI3K, lead to reduced IL-12 expression by DCs, indicating that PI3K plays an important role in the regulation of IL-12 production. We further demonstrated that the lack of PI3K results in an enhanced Th1 response and reduced Th2 response in vivo using L. major and Strongyloides venezuelensis infection model, respectively. Our results show that PI3K play a critical role in determining Thl/Th2 responses in vivo.
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[Journal Article] 「研究成果報告書概要(欧文)」より2006
Author(s)
Yajima, T., Yoshihara, K., Nakazato, K., Kumabe, S., Koyasu, S., Sad, S., Shen, H., Kuwano, H., Yoshikai, Y.
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Journal Title
IL-15 Regulates CD8+ T Cell Contraction during primary Infection. J. Immunol. 176
Pages: 507-515
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[Journal Article] 「研究成果報告書概要(欧文)」より2006
Author(s)
Yu, Y., Nagai, S., Wu, H., Neish, A.S., Koyasu, S., Gewirtz, A.T.
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Journal Title
TLR5-mediated PI3K activation negatively regulates flagellin-induced pro-inflammatory gene expression. J. Immunol. 176
Pages: 6194-6201
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[Journal Article] 「研究成果報告書概要(欧文)」より2006
Author(s)
Ohteki T., Tada, H., Ishida, K., Sato, T., Maki, C., Yamada, T., Hamuro, J., Koyasu, S.
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Journal Title
Essential roles of DC-derived IL-15 as a mediator of inflammatory responses in vivo. J. Exp. Med. 203
Pages: 2329-2338
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[Journal Article] 「研究成果報告書概要(欧文)」より2005
Author(s)
Matsuzawa, A., Saegusa, K., Noguchi, T., Sadamitsu, C., Nishitoh, H., Nagai, S., Kovasu, S., Matsumoto, K., Takeda, K., Ichijo, H.
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Journal Title
ROS-dependent activation of TRAF6-ASK1-p38 pathway is selectively required for TLR4-mediated innate immunity. Nat. Immunol. 6
Pages: 571-578
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[Journal Article] 「研究成果報告書概要(欧文)」より2003
Author(s)
Suzue, K., Asai, T., Takeuchi, T., Koyasu, S.
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Journal Title
In vivo role of IFN-y produced by antigen presenting cells in early host defense against intracellular pathogens. Eur. J. Immunol. 33
Pages: 2666-2675
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[Journal Article] 「研究成果報告書概要(欧文)」より2002
Author(s)
Fukao, T., Yamada, T., Tanabe, M., Terauchi, Y., Ota, T., Takayama, T., Asano, T., Takeuchi, T., Kadowaki, T., Hata, J., Koyasu, S
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Journal Title
Selective loss of gastrointestinal mast cells and impaired immunity in PI3K-deficient mice. Nat. Immunol. 3
Pages: 295-304
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[Journal Article] 「研究成果報告書概要(欧文)」より2002
Author(s)
Fukao, T., Tanabe, M., Terauchi, Y., Ota, T., Matsuda, S., Asano, T., Kadowaki, T., Takeuchi, T., Koyasu, S
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Journal Title
PI3K-mediated negative feedback regulation of IL-12 production in dendritic cells. Nat. Immuno1. 3
Pages: 875-881
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[Journal Article] 「研究成果報告書概要(欧文)」より2002
Author(s)
Murata, Y., Ohteki, T., Koyasu, S., Hamuro, J
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Journal Title
IFN-y production by macrophages and dendritic cells dictated by intracellular thiol redox status. Eur. J. Immunol. 32
Pages: 2866-2873
