The regulation of innate immune responses by dendritic cells through the interaction with microbes

• Project/Area Number: 14021110
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: KEIO UNIVERSITY
• Principal Investigator: KOYASU Shigeo Keio University, School of Medicine, Professor, 医学部, 教授 (90153684)
• Project Period (FY): 2002 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥59,400,000 (Direct Cost: ¥59,400,000); Fiscal Year 2005: ¥16,100,000 (Direct Cost: ¥16,100,000); Fiscal Year 2004: ¥16,100,000 (Direct Cost: ¥16,100,000); Fiscal Year 2003: ¥17,200,000 (Direct Cost: ¥17,200,000); Fiscal Year 2002: ¥10,000,000 (Direct Cost: ¥10,000,000)
• Keywords: IL-12 / IL-15 / IFN-γ / PI3K / Thl / Listeria / Leishmania / nematode / ノックアウトマウス / pDC / インターフェロン / Pten / Th2 / 樹状細胞

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.

Research Products

• [Journal Article] IL-15 Regulates CD8^+ T Cell Contraction during primary Infection. (2006)
  • Author(s): Yajima, T. et al.
  • Journal Title: The Journal of Immunology 176 Pages: 507-515
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] TLR5-mediated PI3K activation negatively regulates flagellin-induced pro-inflammatory gene expression. (2006)
  • Author(s): Yu, Y., et al.
  • Journal Title: The Journal of Immunology 176 Pages: 6194-6201
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Essential roles of DC-derived IL-15 as a mediator of inflammatory responses in vivo. (2006)
  • Author(s): Ohteki, T., et al.
  • Journal Title: The Journal of Experimental Medicine 203 Pages: 2329-2338
  • Description: 「研究成果報告書概要(和文)」より
• [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.
  • Journal Title: IL-15 Regulates CD8+ T Cell Contraction during primary Infection. J. Immunol. 176 Pages: 507-515
• [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.
  • Journal Title: TLR5-mediated PI3K activation negatively regulates flagellin-induced pro-inflammatory gene expression. J. Immunol. 176 Pages: 6194-6201
• [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.
  • Journal Title: Essential roles of DC-derived IL-15 as a mediator of inflammatory responses in vivo. J. Exp. Med. 203 Pages: 2329-2338
• [Journal Article] IL-15 Regulates CD8+T Cell Contraction during Primary Infection. (2006)
  • Author(s): Yajima, T., et al.
  • Journal Title: Journal of Immunology 176 Pages: 507-515
• [Journal Article] Tolerance induction by the blockade of CD40/CD154 interaction in pemphigus vulgaris mouse model. (2006)
  • Author(s): Aoki-Ota, M., et al.
  • Journal Title: Journal of Investigative Dermatology 126 Pages: 105-113
• [Journal Article] ROS-dependent activation of TRAF6-ASK1-p38 pathway is selectively required for TLR4-mediated innate immunity. (2005)
  • Author(s): Matsuzawa, A., et al.
  • Journal Title: Nature Immunology 6 Pages: 571-578
  • Description: 「研究成果報告書概要(和文)」より
• [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.
  • Journal Title: ROS-dependent activation of TRAF6-ASK1-p38 pathway is selectively required for TLR4-mediated innate immunity. Nat. Immunol. 6 Pages: 571-578
• [Journal Article] Exogenous antigens are processed through the endoplasmic reticulum-associated degradation (BRAD) in cross-presentation by dendritic cells. (2005)
  • Author(s): Imai, J., et al.
  • Journal Title: International Immunology 17 Pages: 45-53
• [Journal Article] Negative feedback loop in T cell activation through MAPK-catalyzed threonine phosphorylation of LAT. (2004)
  • Author(s): Matsuda, S., et al.
  • Journal Title: EMBO Journal 23 Pages: 2577-2585
• [Journal Article] Auto-reactive B cells against peripheral antigen, desmoglein 3,escape from tolerance mechanism. (2004)
  • Author(s): Ota, T., et al.
  • Journal Title: International Immunology 16 Pages: 1487-1495
• [Journal Article] In vivo role of IFN-γ produced by antigen presenting cells in early host defense against intracellular pathogens. (2003)
  • Author(s): Suzue, K., et al.
  • Journal Title: European Journal of Immunology 33 Pages: 2666-2765
  • Description: 「研究成果報告書概要(和文)」より
• [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.
  • 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
• [Journal Article] Selective loss of gastrointestinal mast cells and impaired immunity in PI3K-deficient mice. (2002)
  • Author(s): Fukao, T., et al.
  • Journal Title: Nature Immunology 3 Pages: 295-304
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] PI3K-mediated negative feedback regulation of IL-12 production in dendritic cells. (2002)
  • Author(s): Fukao, T., et al.
  • Journal Title: Nature Immunology 3 Pages: 875-881
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] IFN-γ production by macrophages and dendritic cells dictated by intracellular thiol redox status. (2002)
  • Author(s): Murata, Y., et al.
  • Journal Title: European Journal of Immunology 32 Pages: 2866-2873
  • Description: 「研究成果報告書概要(和文)」より
• [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
  • Journal Title: Selective loss of gastrointestinal mast cells and impaired immunity in PI3K-deficient mice. Nat. Immunol. 3 Pages: 295-304
• [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
  • Journal Title: PI3K-mediated negative feedback regulation of IL-12 production in dendritic cells. Nat. Immuno1. 3 Pages: 875-881
• [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
  • Journal Title: IFN-y production by macrophages and dendritic cells dictated by intracellular thiol redox status. Eur. J. Immunol. 32 Pages: 2866-2873
• [Publications] Suzue, K., et al.: "In vivo role of IFN-γ produced by antigen presenting cells in early host defense against intracellular pathogens."The European Journal of Immunology. 33. 2666-2675 (2003)
• [Publications] Esashi, E., et al.: "A possible role for CD4^+ thymic macrophages as professional scavengers of apoptotic thymocytes."The Journal of Immunology. 171. 2773-2777 (2003)
• [Publications] Suzuki, H., et al.: "PI3K and Btk differentially regulate B cell antigen receptor mediated signal transduction."Nature Immunology. 4. 280-286 (2003)
• [Publications] Nakaoka, Y., et al.: "Activation of gp130 transduces hypertrophic signal through interaction of scaffolding/docking protein Gab1 with tyrosine phosphatase SHP2 in cardiomyocytes."Circulation Research. 93. 221-229 (2003)
• [Publications] Fukao, T., et al.: "PI3K-mediated negative feedback regulation of IL-12 production in dendritic cells"Nat. Immunol.. 3. 872-881 (2002)