Dr. Shimizu is focused on trying to understand how immune responses are generated and how that information can be used in the clinic to improve patient care. He and his colleagues are particularly interested in identifying the general principles by which the T-cell response is initiated. These cells require contact with other cells order to become activated and play their role in an antigen-specific immune response. Cellular adhesion processes and cell-surface receptors transmit biochemical signals inside the cells that lead to T-cell activation and differentiation into cytotoxic T cells or helper T cells. Cellular adhesion spurs efficient trafficking of lymphocytes through the body and their influx to inflammatory sites. Shimizu's laboratory is investigating the signaling pathways that regulate the strength of these adhesive interactions. His team is also exploring the functional significance of these T-cell molecular mechanisms and their role in the ability of the immune system to respond to pathogens and tumors.
Shimizu has a long-standing and continuing research interest in the role of integrins in T-cell adhesion and activation. The integrins are a superfamily of cell adhesion receptors that T-cells use to carry out many of their normal functions, including their ability to migrate to sites in the body where they are needed. Shimizu and his University colleagues have identified novel signaling intermediates that promote integrin function and T-cell activation, and are currently investigating the role of integrins in controlling the localization of T-cells to specific anatomic sites in the body. Of particular interest is the tumor microenvironment, which is normally immunosuppressive and thus dampens the ability of T-cells to recognize and kill tumor cells. Sophisticated imaging technologies such as two-photon microscopy now make it possible to track the movement and behavior of T-cells in the normal and tumor tissue microenvironments. Currently, Shimizu and colleagues are using this technology to analyze the behavior of cytotoxic T-cells in the tumor microenvironment and the role of integrins and immune checkpoint blockade in controlling T-cell movement and retention in the tumor microenvironment. Signal transduction, lymphocyte activation, cell adhesion and migration The generation of an antigen-specific immune response requires the coordinated interaction of the various cellular constituents of the immune system with each other and with components of the extracellular environment found in tissue. These adhesive events are critical to the efficient trafficking of lymphocytes through the body, the interaction of T lymphocytes with antigen-presenting cells that initiates and sustains T cell activation, and the influx of leukocytes into sites of inflammation. Dr. Shimizu's laboratory is investigating the intracellular signal transduction events that regulate the strength of these adhesive interactions and the functional significance of these molecular mechanisms of cell adhesion and migration on the ability of the immune system to respond to pathogens and tumors. Specific areas of investigation projects include: Analysis of the biochemical signaling events by which the antigen-specific T cell receptor regulates the functional activity of integrins, a family of cell adhesion receptors that mediates the adhesion of cells to other cells and to extracellular matrix molecules Mechanisms of receptor "cross-talk" that regulate integrin function The function of adapter proteins in regulating T cell gene transcription and cytoskeletal reorganization Elucidation of pathways mediating the migration and retention of tumor-specific T cells into sites of tumor growth Analysis of the function of the lipid kinase p110gamma in regulating the inflammatory response and T cell-dependent immune responses to vaccinia virus. Dr. Shimizu's laboratory combines molecular and biochemical approaches with genetic models in the mouse where the impact of altering signaling pathways on the generation of antigen-specific and tumor-specific immune responses can be assessed. The long-term objective is to provide the knowledge base necessary to specifically modulate the immune response by targeting these mechanisms of cell adhesion and migration.
- Domae, E., Hirai, Y., Ikeo, T., Goda, S., and Shimizu, Y.: Cytokine-mediated activation of human ex vivo-expanded Vg9Vd2 T cells. Oncotarget 2017; 8:45928-45942.
- Banek, C.T., Kneupfer, M.M., Foss, J.D., Fiege, J.K., Asirvatham-Jeyaraj, N., Van Helden, D., Shimizu, Y., and Osborn, J.W. Resting afferent renal nerve discharge and renal inflammation: elucidating the role of afferent and efferent renal nerves in deoxycorticosterone acetate salt hypertension. Hypertension 2016; 68:1415-1423.
- Asirvatham-Jeyaraj, N., Fiege, J.K., Han, R., Foss, J., Banek, C.T., Burbach, B.J., Razzoli, M., Bartolomucci, A., Shimizu, Y., Panoskaltsis-Mortari, A., and Osborn, J.W.: Renal denervation normalizes arterial pressure with no effect on glucose metabolism or renal inflammation in obese hypertensive mice. Hypertension 2016; 68:929-936.
- Wang, H., Kwak, D., Fassett, J., Hou, L., Xu, X., Burbach, B., Thenappan, T., Xu, Y., Ge, J., Shimizu, Y., Bache, R., and Chen, Y.: CD28/B7 deficiency attenuates systolic overload-induced congestive heart failure, myocardial and pulmonary inflammation, and activated T-cell accumulation in the heart and lungs. Hypertension 2016; 68:688-696.
- Fiege, J.K., Beura, L.K. and Shimizu, Y.: Adhesion and degranulation promoting adapter protein (ADAP) promotes CD8 T cell differentiation and resident memory formation and function during an acute infection. J. Immunol. 2016; 197: 2079-2089.
- Mitchell, J.S., Burbach, B.J., Srivastava, R., Fife, B.T. and Shimizu, Y.: Multi-stage T cell-dendritic cell interactions control optimal CD4 T cell activation through the ADAP-SKAP55 signaling module. J. Immunol. 2013; 191:2372-2383. PMCID: PMC3772631.
- Zumwalde, N.A., Domae, E., Mescher, M.F. and Shimizu, Y.: ICAM-1 dependent homotypic aggregates regulate CD8 T cell effector function and differentiation during T cell activation. J. Immunol. 2013; 191:3681-3693. PMCID: PMC3803108.
- Srivastava, R., Burbach, B.J., Mitchell, J.S., Pagan, A.J. and Shimizu, Y.: ADAP regulates cell cycle progression of T cells via control of cyclin E and cdk2 expression through distinct CARMA1-dependent signaling pathways. Mol. Cell. Biol. 2012; 32:1908-1917. PMCID: PMC3347422.