Polarization, the sub-cellular localization of cellular components such as receptors, signaling intermediates, vesicles and the cyotskeleton, is a fundamental element of cell regulation. It is particular important in the activation of immune cells. T cells are the central regulatory cells of the adaptive immune response. NK cells are critical effectors of the innate immune response. Both are activated in an interaction with a second cell, the antigen presenting or target cell, respectively. Both subsequently polarize towards the cellular interface as a central element of their function in a structure called the immunological synapse. In our laboratory, we visualize lymphocyte polarization using 3D live cell video fluorescence microscopy, we try to understand the significance of particular polarization events, and elucidate their regulation. We emphasize the visualization and manipulation of small signal transduction chains and networks. As T and NK cells, despite sunstantial homologies in their signal transduction machineries, polarize to very different extents, investigating both in parallel is particularly informative.
Our current efforts to understand lymphocyte polarization and its regulation focus on two questions. First, the dynamics of the central cytoskeletal component actin are critical for polarization. They are well understood in various cell system but not so in lymphocytes. In collaborations with Michael K. Rosen (on molecular mechanisms of actin regulation) and John D. Schatzle (on NK cell cytoskeletal dynamics), we study the regulation of T and NK cell actin dynamics. An important hypothesis that we test in these studies is that the polarization of regulators of actin dynamics is a critical element of lymhpocyte actin regulation. Second, efficient T cell activation requires engagement of the T cell receptor as the receptor to confer antigen specificity and of costimulatory receptors in parallel. The two dominant costimulatory receptors are CD28 and LFA-1. We have established that, as part of their mechanism of action, these costimulatory receptors regulate various aspects of T cell polarization. We, therefore, study costimulatory signal transduction in comparison to that of the T cell receptor in a collaboration with Nicolai van Oers.
While our laboratory currently focuses on the elucidation of molecular and cellular mechanism regulating lymphocyte polarization, the application of new insight in mouse models of disease is often straightforward. In one such application, we attempt to promote the anti-tumor activity of NK cells by enhancing their polarization.
RESEARCH INTERESTS
T cell polarization in T cell activation
NK cell polarization in NK cell-mediated cytolysis
The immunological synapse
Signal transduction in the regulation of lymphocyte polarization
RECENT PUBLICATIONS
Wulfing, C., Klem, J., Purtic, B., and Schatzle, J. D., "Stepwise cytoskeletal polarization as a series of checkpoints in innate but not adaptive cytolytic killing." Proc. Natl. Acad. Sci. USA, 100:7767, Summer 2003
Purtic, B., Pitcher, L. A., van Oers, N. S. C., and Wulfing, C., "T cell receptor (TCR) clustering in the immunological synpase integrates TCR and costimulatory signaling in selected T cells" Proc. Natl. Acad. Sci. USA, 102:1904-9, February 2005
I. Tskvitaria-Fuller, A. Seth, N. Mistry, H. Gu, M.K. Rosen, and C. Wulfing, "Specific Patterns of Cdc42 Activity Are Related to Distinct Elements of T cell Polarization" J. Immunol., 177:1708, August 2006
Singelton, K., Parvaze, N., Dama, K. R., Chen, K. S., Jennings, P., Purtic, B., Sjaastad, M. D., Gilpin, C., Davis, M. M., and Wulfing, C., "A large T cell invagination with CD2 enrichment resets receptor engagement in the immunological synpase" J. Immunol., 177:4402-13, October 2006
Tskvitaria-Fuller, I., Mistry, N., Sun, S., and Wulfing, C., "Protein transduction as a means of effective manipulation of Cdc42 activity in primary T cells" J. immunol. Methods, 319:64-78, January 2007
SIGNIFICANT PUBLICATIONS
Wulfing, C., Sumen, C., Sjaastad, M. D., Wu, L. C., Dustin, M. L., and Davis, M. M., "Costimulation and endogenous MHC ligands contribute to T cell recognition." Nat. Immunol., 3:42, January 2002
Wulfing, C., Klem, J., Purtic, B., and Schatzle, J. D., "Stepwise cytoskeletal polarization as a series of checkpoints in innate but not adaptive cytolytic killing." Proc. Natl. Acad. Sci. USA, 100:7767, June 2003
Purtic, B., Pitcher, L. A., van Oers, N. S. C., and Wulfing, C., "T cell receptor (TCR) clustering in the immunological synapse integrates TCR and costimulatory signaling in selected T cells" Proc. Natl. Acad. Sci. USA, 102:2904-9, 2005
I. Tskvitaria-Fuller, A. Seth, N. Mistry, H. Gu, M.K. Rosen, and C. Wulfing, "Specific Patterns of Cdc42 Activity Are Related to Distinct Elements of T cell Polarization" J. Immunol., 177:1708-20, August 2006
Singelton, K., Parvaze, N., Dama, K. R., Chen, K. S., Jennings, P., Purtic, B., Sjaastad, M. D., Gilpin, C., Davis, M. M., and Wulfing, C., "A large T cell invagination with CD2 enrichment resets receptor engagement in the immunological synapse" J. Immunol., 177:4402-13, October 2006
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