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Makio Iwashima, Ph.D.
E-mail:
Research Emphasis:
My research focuses on two aspects of the immune system. One is
immunological tolerance and the other is immunological memory. Tolerance is
achieved by several mechanisms and a major process is thymic selection where
self-reactive precursor T cells are removed. The other is peripheral tolerance
by which self-reactive T cells get functionally suppressed. Memory is
maintained by establishment of memory cells that carry the information of
antigens after antigenic stimulation. In all cases, recognition of antigen by T
cells play critical roles to determine the fate of each T cell clone and
ultimately establish the repertoire of the immune system.
To understand immunological tolerance at molecular level, we analyze the signaling process of T cell antigen receptor(TCR). One of our current project is to elucidate the signaling pathway that controls gene expression of T cell cytokines such as IL-2, which is a factor that enhances and supports T cell growth and immunological response. This study will provide us the information regarding how TCR functions in mature T cells. In the future, we will extend this project and characterize how these signaling pathways function in thymic development and peripheral tolerance.
To understand immunological memory, we are establishing a mouse model which allows us to detect T cells which experienced antigenic stimulation. We will identify and characterize genes that are specifically expressed in T cells that are exposed to antigens. By identifying such genes, we will be able to characterize how T cells acquire the ability to maintain the information of exposure to antigens.
Completion of studies will contribute to understand how immune system maintains its ability to remove infectious agents while avoiding destructive reactivity against self. This, in turn, will help to develop effective treatment and drug discovery for autoimmune diseases and immuno-deficiency, and will provide tools to activate T cell in antigen specific manners for eradication of chronic infections and tumors.
Selected Publications:
Iwashima, M., Irving, B., van Norse, N.,
Chan, A. and Weiss, A. (1994) Sequential interactions of the TCR with two
distinct cytoplasmic tyrosine kinases. Science 263,
1136-1139.
Chan, A.C., Kadlecek, T.A., Elder, M.E., Filipovich, A.H., Kuo, W., Iwashima,
M., Parslow, T.G. and Weiss, A. (1994) ZAP-70 deficiency in an autosomal
recessive form of severe combined immunodeficiency. Science 264, 1599-1601.
Yamasaki, S, Takamatsu, M. and Iwashima, M. (1996) The kinase, SH3 and SH2
domains of Lck play critical roles for T cell activation after ZAP-70 membrane
localization. Mol. Cell. Biol. 16, 7151-7160.
Yamasaki, S., Tachibana, M., Shinohara, N., and Iwashima, M. (1997) Lck
independent triggering of T cell antigen receptor signal transduction by
Staphylococcal enterotoxins. J. Biol. Chem., 272, 14787-14791.
Huby, R.D.J., Iwashima, M., Weiss, A., and Ley, S. (1997). ZAP-70 protein
tyrosine kinase is constitutively targeted to the T cell cortex independently of
its SH2 domains. J. Cell Biol., 137, 1639-1649.
Fujimaki, W., Iwashima, M., Yagi, J., Zhang, H., Yagi, H., Seo, K., Imai, Y.,
Imanishi, K., and Uchiyama, T. Functional uncoupling of TCR engagement and Lck
activation in thymic mature CD4 single positive T cells. (2001) J Biol.
Chem. 276:17455-17460.
Iwashima, M., Takamatsu, M, Yamagishi,H., Huang, Y., McGinty, C., Hatanaka,
Y., Yamasaki, S., and Koike, T. Genetic evidence for Shc requirement in TCR
induced c-Rel activation and IL-2 expression. (2002) Proc. Natl. Acad. Sci.
USA 99:4544-4549.
Iwashima, M. Kinetic perspectives of T cell activation. (2003)
Immunol. Rev. 192. 196-210.
Koike, T., Yamagishi, H., Hatanaka Y., Fukushima A., Chan, J.W., Xia,
Y., Fields, M., Chandler, P., and Iwashima, M. A novel ERK dependent
signaling process that regulates IL-2 expression in a late phase of T
cell activation. (2003) J. Biol. Chem. in press