The specificity and sensitivity of T-cell recognition is vital to the immune response. The interaction of the T-cell receptor (TCR) with peptide-major histocompatibility complexes (MHC) and signaling through the TCR:CD3 signaling complex results in T-cell activation and the initiation of a cellular immune response. In nature, cytotoxic T-cells are responsible for identifying cells that display foreign or aberrant antigens and killing them and thus have long been recognized for their potential in the immunotherapy of cancer. There is a fundamental gap in the understanding what molecular and cellular mechanisms are required for T cell-mediated tumor cell destruction. Lack of such knowledge is an important problem, because, without it, development of successful cancer vaccines that induce, strengthen and increase the duration of immunological attack against cancer cells will be very difficult to achieve. We are using novel imaging and biophysical methods to offer new insights into how robust and functional T-cell responses can be generated against self antigens both in vitro and in vivo with the goal of designing new and innovative approaches to the prevention and treatment of cancer. In addition our research may be pertinent to the development of therapeutic proposals for treatment of viral infections that induce T-cell tolerance e.g. HIV and chronic hepatitis. Conversely, such information could also be of great importance with respect to autoimmunity, which is the "other side of the coin" where less T-cell responsiveness is desired to avoid autoreactivity. Supported by the Pew Trust, Cancer Research Institute (CRI) and The Arthritis Foundation, New York Chapter and NIGMS/NIH.