Combined Program on Microbiology and Immunology. Osaka University.

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Research Theme :
Regulation of immune responses by modulation of lymphocyte homing

Principle Research Scientist
Masayuki Miyasaka
Profile:

1974 Assistant Professor, Internal Medicine, Kanazawa Medical University
1977-1981 PhD course, John Curtin School of Medical Research, The Australian National University, Canberra, Australia
1981 PhD in Immunology from the Australian National University
1981-1986 Member, Basel Institute for Immunology
1987-1992 Head, Department of Immunology, The Tokyo Metropolitan
Institute of Medical Science
1993-2001 Professor, Osaka University School of Medicine
2001- Professor, Osaka University Graduate School of Medicine
Other Chairman, Ph.D. program committee, Osaka University Graduate
School of Medicine

Collaborators

Toshiyuki Tanaka

Research Summary

Lymphocytes continuously travel from the blood to secondary lymphoid tissues and then return to the blood. This phenomenon, which is termed lymphocyte recirculation, is essential for the generation and propagation of immune responses and ensures the coordinated expression of immunological functions by the lymphoid tissues in vivo. In lymph nodes and Peyer’s patches, the recirculation process is initiated by lymphocytes adhering to and migrating across specific blood vessels, high endothelial venules (HEVs). Within the lymphoid tissues, lymphocytes require precise positioning so that they can meet and interact with various cells and humoral factors to properly perform their functions. Accumulating evidence indicates that cell migration events into and within lymphoid organs are under the control of a family of small basic chemotactic proteins, chemokines. Chemokines bind to heptahelical receptors coupled to G?i and activate intracellular signaling pathways. Some chemokines are expressed in tissue- or microenvironment-specific manners, imparting at least certain lymphocyte subsets a specific tropism for these tissues or microenvironments. Despite significant advances in our understanding of chemokine-induced mobilization of lymphocytes, a number of questions remain unanswered. For instance, although multiple chemokines are thought to be required for the navigation of a lymphocyte into a certain tissue microdomain, it is unclear how many chemokines and in what sequential order the chemokines must be encountered by a lymphocyte before it is guided into the right place. It is also unknown whether a lymphocyte responds to chemokines one at a time or simultaneously in vivo. More fundamentally, although the term chemotaxis implies that lymphocytes undergo directed motion in a chemokine gradient, it has not been firmly established whether lymphocytes really move toward the source of a chemokine in vivo. Furthermore, the existence of chemokine gradients has not been demonstrated in vivo. Understanding these basic questions will help elucidate efficient methods for the induction of immune responses toward various infectious agents.

Lymphocytes continuously traffic into lymph nodes where the interaction between the innate and adaptive immune responses occurs. Understanding of the molecular mechanisms underlying lymphocyte homing is critical for the development of strategies for induction of effective immune responses against pathogens.

Publications

1. Nagakubo, D., Murai, T., Tanaka, T., Usui, T., Matsumoto, M., Sekiguchi, K. &
Miyasaka, M.: A high endothelial venule secretory protein, mac25/angiomodulin, interacts with multiple high endothelial venule-associated molecules including chemokines. J.Immunol., 171:553-561, 2003.

2. *Ebisuno, Y., *Tanaka, T., Kanemitsu, N., Kanda, H., Yamaguchi, K., Kaisho, T.,
Akira, S. & Miyasaka, M. (*equal contribution): Cutting Edge: The B cell chemokine CXCL13/B-lymphocyte chemoattractant is expressed in the high endothelial venules of lymph nodes and Peyer’s patches and affects B cell trafficking across high endothelial venules. J.Immunol., 171:1642-1646, 2003.

3. Kawashima, H., Atarashi, K., Hirose, M., Hirose, J., Yamada, S., Sugahara, K. &
Miyasaka, M.; Oversulfated chondroitin/dermatan sulfates containing GlcA?1/IdoA?1-3GalNAc(4,6-O-disulfate) interact with L- and P-selectin and chemokines. J.Biol.Chem., 277:12921-12930. [2002].

4. Hirose, J., Kawashima, H., Yoshie, O., Tashiro, K. & Miyasaka, M.: Versican
interacts with chemokines and modulates cellular responses. J.Biol.Chem., 276:5228-5234, 2001.

5. Kawashima, H., Hirose, M., Hirose, J., Nagakubo, D., Plaas, A.H.K. & Miyasaka,
M.: Binding of a large chondroitin sulfate/dermatan sulfate proteoglycan, versican, to L-selectin, P-selectin and CD44. J.Biol.Chem., 275:35448-35456, 2000.