Combined Program on Microbiology and Immunology. Osaka University.

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Research Theme :
Analysis of the host response mediated by immune semaphorins

Principal Research Scientist
Hitoshi Kikutani
Profile:

April, 1975 – 1979
Ph.D. candidate at Osaka University, Graduate School of Medicine
April - September, 1979
Research Fellow and Physician, Osaka University, School of Medicine, Internal Medicine Department 3
October, 1979 - September, 1981
Visiting Research Fellow, Memorial Sloan-Kettering Cancer Center
October, 1981 - March, 1982
Research Fellow and Physician, Osaka University, School of Medicine, Internal Medicine Department 3
April, 1982 – March, 1983
Post-Doctoral Research Fellow, Japan Society for the Promotion of Science
April - July, 1983
Physician, Osaka University, School of Medicine, Internal Medicine Department 3
July, 1983
Research Associate, Osaka University, Institute for Molecular and Cellular Biology (Cellular Immunology)
November, 1989
Associate Professor, Osaka University, Institute for Molecular and Cellular Biology (Cellular Immunology)
November, 1996
Professor, Research Institute of Microbial Diseases, Osaka University (Molecular Immunology)

Collaborators

Masayuki Mizui (Postdoctral Fellow of COE)

Research Summary

From the time it is elicited to the time it comes to an end, the immune response is controlled in a highly sophisticated manner through interactions among immunocompetent cells. Such intercellular communication is mediated by molecules including soluble factors such as cytokines and chemokines, adhesive molecules such as the integrin family, and co-stimulating molecules including the B7 and TNF families such as the B7 and CD40 ligands. However, the immune response in living organisms involves a series of complex reactions and intracellular cascades, and cannot be explained simply by the interactions of these ligand molecules. Our recent research has suggested that a member of the semaphorin family known to be a guidance factor plays a crucial role in neural circuit formation. For example, CD100/Sema4D, which belongs to the class IV semaphorin subfamily, regulates activation of antigen-presenting cells including B cells and dendritic cells. This regulation occurs through a unique mechanism which turns off CD72-receptor-mediated inhibitory signal transduction. We have also elucidated the following: 1) the class IV semaphorin, Sema4A, is expressed in dendritic cells, and binds Tim-2 receptor and enhances T cell activation, and 2) in vivo administration of anti-Sema4A monoclonal antibody inhibits the priming of antigen-specific T cells and the onset of experimental autoimmune encephalomyelitis (EAE). Furthermore, in addition to CD100/Sema4D and Sema4A, Sema3A, Sema4B, Sema4G, Sema6B, Sema6D, and Sema7A are expressed on immune cells, and we found that some members of the family possess biological activities on the immune cells and elicit immune responses. As described above, the physiological significance of semaphorins in the immune system has been demonstrated for the first time through our research. Therefore, we currently focus on 1) conducting comprehensive and systematic analyses on the function of the semaphorins which are expressed in the immune system, their receptors, and signaling, 2) establishing a novel paradigm for semaphorin-mediated immune regulation, and 3) endeavoring to develop therapeutic treatments for immune diseases by molecular targeting of immune semaphorins.

Publications

1. Kikutani H, and A. Kumanogoh. Semaphorins in interactions between T cells and antigen-presenting cells. Nat Rev Immunol., 3:159-67, 2003.

2. Kumanogoh, A., S. Marukawa, K. Suzuki, N. Takegahara, C. Watanabe, E.-S. Ch'ng, I. Ishida, H. Fujimura, S. Sakoda, Ka. Yoshida, and H. Kikutani. Class IV semaphorin Sema4A semaphorin enhances T cell activation and interacts with Tim-2. Nature, 419:629-633, 2002.

3. Kumanogoh, A., C. Watanabe, I. Lee, X.-S.. Wang, W. Shi, H. Araki, H. Hirata, K. Iwahori, J. Uchida, T. Yasui, M. Matsumoto, Ka. Yoshida, H. Yakura, C. Pan, J.R. Parnes, and H. Kikutani. Identification of CD72 as a lymphocyte receptor for the class IV semaphorin CD100: A novel mechanism for regulating B cell signaling. Immunity, 13:621-631, 2000.

4. Shi, W., A. Kumanogoh, C. Watanabe, J. Uchida, X.-S.. Wang T. Yasui, K. Yukawa, M.
Ikawa, M. Okabe, J.R. Parnes. Ka. Yoshida, and H. Kikutani. The class IV semaphorin CD100 plays a nonredundant role in the immune system: Defective B and T cell activation in CD100-deficient mice. Immunity, 13:633-642, 2000.

5. Uchida, J., T. Yasui, Y. Takaoka-Schichijo, M. Muraoka, W. Kulwichit, N. Raab-Traub, and H. Kikutani. Mimicry of CD40 signals by Epstein-Barr virus LMP1 in B lymphocyte responses. Science, 286:300-303, 1999.