The long-term goal of our studies is to understand the complex physiological 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. 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 respond properly to engagement of their T Cell Receptors (TCRs) are still unclear. Using a combination of biochemical, genetic and novel multi-dimensional digital imaging approaches we study complex multi dimensional signal integration rather than signal dissection during the interaction of T cells with live antigen-presenting cells (APCs). Protein Kinase C-theta was identified as the first key protein that serves as master switch for determining the physiological outcome to initial T cell activation. These studies identified the previously unknown structure of the Immunological-Synapse that 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.

Kupfer, A. and Kupfer, H. (2003) Imaging immune cell interactions and functions: SMACs and the immunological synapse. Seminars in Immunology 19:4712-4722 [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. 18:6201–6208 [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 92:819–828 [PubMed]

Kupfer, A. (2000) Breaking up receptor alliances: the parting of CD3 and CD4. Nature Medicine 16:2248–2254 [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 166:4773-4779 [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]