Research Topic: Signaling, cell-cell interaction, intercellular communication, immune cell activation, multi-dimensional imaging, novel biosensors
The long-term goal of our studies is to understand the complex cellular and molecular mechanisms of inter- and intra-cellular communication in the immune system. T cells play a central role in regulating the cellular and humoral responses towards invading pathogens and malignant transformation. On the flip side, improper recognition of self-antigens by T cells is the primary cause of most autoimmune diseases. The critical molecular and cellular mechanisms that the T cells use to sense their environment and how this sensing is relayed into a particular functional response are still unclear.
Using a combination of molecular biology, biochemical and novel multi-dimensional digital imaging approaches we study in real-time complex multi dimensional signal integration during the interaction of T cells with live antigen-presenting cells. These studies led to the discovery of the Immunological-Synapse. This synapse is composed of different Supra-Molecular Activation Clusters (SMACs) of receptors, cytoskeletal and signaling proteins. We continue to study the 4-dimensional structure and function of the dynamic SMACs and their roles in regulation of the immune response. We identified Protein Kinase C-theta as the first key protein that serves as master switch for determining the physiological outcome to initial T cell activation. Using retroviral infection of T cells we designed a new biosensor for the c-SMAC of the Synapse. We are using now a genetic yeast two-hybrid screen with this biosensor to identify new proteins that are important for the structure and function of the Immunological Synapse.
Kupfer, A. and Kupfer, H. (2003) Imaging immune cell interactions and functions: SMACs and the immunological synapse. Seminars in Immunology 19:4712-4722.
Freiberg, B. A., Kupfer, H., Maslanik, W., Delli, J., Kappler, J., Zaller, D.M. and Kupfer, A. (2002) Staging and resetting T cell activation in SMACs. Nat. Immunol. 18:6201-6208.
Potter, T.A., K. Grebe, B. Freiberg, and Kupfer, A. (2001) Formation of supramolecular activation clusters on fresh ex vivo CD8+ T cells after engagement of the T cell antigen receptor and CD8 by antigen-presenting cells. Proc. Natl. Acad. Sci. USA 92:819-828.
Kupfer, A. (2000) Breaking up receptor alliances: the parting of CD3 and CD4. Nature Medicine 16:2248-2254.
Monks, C.R.F., B.A. Freiberg, H. Kupfer, N. Sciaky, and Kupfer, A. (1998) Three-dimensional segregation of supramolecular activation clusters in T cells. Nature 166:4773-4779.
Monks, C.R.F., Kupfer, H., Tamir, I., Barlow, A., and Kupfer, A. (1997) Selective modulation of protein kinase C-theta during T-cell activation. Nature 46 (Suppl): S67-S72.