Our group is studying on the molecular mechanisms of activation and homeostasis of T cells in order to be able to modulate T cell activation/function in immunological disorders. Particularly in this center, we are analyzing the dynamic regulation of signal molecules in a single cell level by utilizing a combination of genetic and imaging approaches.
(1) Dynamic regulation of antigen recognition and activation of T cells.
We have studied the dynamic movement of signaling molecules in the process of the formation of the immunological synapse and T cell activation upon antigen recognition. Using single-molecule imaging technique, we visualized dynamic process of T cell activation at single molecule level. We have visualized the entire process of immunological synapse formation by visualizing, and as the receptor (CD3ζ), kinase (ZAP-70) and adaptor (SLP-76) in the TCR signaling complex. Consequently, we found that microclusters containing TCR, kinases and adaptors are generated and function as the unit for antigen recognition and activation of T cells. We are then revising the current model of T cell activation from the view of TCR microcluster. The molecules assemblies in the microclusters were analyzed. Particularly, we are analyzing the temporal and spatial regulation of co-stimulation signals and contribution of lipid raft on T cell activation.
(2) Signal interface regulating innate and acquired immune signaling
Antigen receptor signals are mediated through ITAM-bearing adaptors associated with T and B cell receptors in lymphocytes. We analyzed signaling through ITAM-associated receptors expressed on myeloid cells for NF-κB activation such as FcγR, TREM, OSCAR as well as TLR function on lymphoid cells to understand the crosstalk between innate and acquired immunities. We found that while lymphocytes utilize the CARMA1-Bcl10 complex for IKK and NF-κB activation, myeloid cells use the CARD9-Bcl10 complex for ITAM-associated receptor-mediated NF-κB activation. The differential usage of the adaptors CARMA1 vs. CARD9 appears to be cell type-specific.
Takashi Saito Guest Professor
Molecular imaging of a T cell activation and differentiation
|1982||Ph.D., Chiba University Graduate School of Medicine|
Research and career history
|1988||Assistant Professor, Chiba University|
|1989||Lecturer, Chiba University|
|1989||Professor, Chiba University|
|1996||Director, Chiba University, Center for Biomedical Sciences|
|2001||Group Director, RIKEN, Research Center for Allergy & Immunology|
|2005||Deputy Director, RIKEN, Research Center for Allergy & Immunology|
Takashi Saito Guest Professor
- Liang Y., Cucchetti M., Roncagalli R., Yokosuka T., Malzac A., Bertosio E., Imbert J., Nijman I.J., Suchanek M., Saito T., Wulfing C., Malissen B. and Malissen M.: Rltpr, a lymphoic lineage-specific actin-uncapping protein is essential for CD28 costimulation and regulatory T cell development. Nat. Immunol. in press.
- Kawashima T, Kosaka A., Yan H., Zijin G., Uchiyama R., Fukui R., Kaneko D., Kumagai Y., You D-J., Carreras J., Uematsu S., Jan M.H., Takeuchi O., Kaisho T., Akira S., Miyake K., Tsutsui H., Saito T., Nishimura I. and Tsuji N.M.: Double-stranded RNA of small intestinal commensal but not pathogenic bacteria triggers TLR3-mediated IFNβ production by dendritic cells. Immunity. In press.
- Tsukumo, S-I., Unno, M., Muto, A., Takeuchi, A., Kometani, T., Kurosaki, T., Igarashi, K. and Saito,T.: Bach2 maintains T cells in a naive state by suppressing effector memory-related genes. Proc Natl Acad Sci USA. 110(26): 10735-10740, 2013.
- Yamaguchi, T., Kishi, A., Osaki, M., Morikawa, H., Prieto-Martin, P., Wing, K., Saito, T. and Sakaguchi, S.: Construction of self-recognizing regulatory T cells from conventional T cells by controlling CTLA-4 and IL-2 expression. Proc. Nat. Acad. Sci. USA. 110(23):E2116-E2125, 2013.
- Ishikawa, T., Itoh, F., Yoshida, S., Saijo, S., Matsuzawa, T., Gonoi, T., Saito, T., Okawa, Y., Shibata, N., Miyamoto, T. and Yamasaki, S.: Identificiation of distinct ligands for Mincle and Dectin-2 in the pathogenic fungus Malassezia. Cell Host & Microbe. 13(4): 477-488, 2013.
- Jiang, Y., Arase, N., Kohyama, M.,Hirayasu, K., Suenaga, T., Jin H., Matsumoto, M., Shida, K., Lanier, L.L., Saito, T. and Arase, H.: Transport of misfolded endoplasmic reticulum proteins to the cell surface by MHC class II molecules. Int. Immunol. 25(4):235-246, 2013.