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.

Publications:

Kupfer, A. and Kupfer, H. (2003) Imaging immune cell interactions and functions: SMACs and the immunological synapse. Seminars in Immunology 15(6):295-300.
PubMed

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. 3(10):911-7
PubMed

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 98(22):12624-9.
PubMed

Kupfer, A. (2000) Breaking up receptor alliances: the parting of CD3 and CD4. Nature Medicine 6(10:1097-8.
PubMed

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 3;395(6697):82-6.
PubMed

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.
PubMed