Sensitivity of T-cell activation
My laboratory is studying how robust and functional T-cell responses can be generated against cancer ('self') antigens. So far our understanding of the molecular and cellular mechanisms required for T cell mediated tumor destruction is incomplete as evidenced by the largely ineffective use of T cell therapies to combat cancer. Our work seeks to characterize both the strength of the interaction between a T-cell and its target as well as its stimulatory environment which is important for setting the threshold for a functional T-cell response against tumors. Another aspect of our work is to record directly and in real time the conformational changes of the receptor protein that lead to its activation under physiologic conditions. To accomplish this we employ advanced and highly innovative methods that combine state-of-the-art biophysical for characterizing protein-protein interactions e.g. surface plasmon resonance (SPR), X-ray crystallography infrared (IR) and nuclear magnetic resonance (NMR) spectroscopy with imaging methods and transgenic TCR technologies to allow for quantification T-cell sensitivity to cancer antigens which makes our research highly interdisciplinary in its nature. This information is important not only for understanding the activation of signaling pathways important for T cell function but also for the purpose of modulating signaling through the TCR pharmacologically in new and innovative approaches. This is with the purpose of increasing the sensitivity of T-cells in patients with cancer or HIV and decreasing the sensitivity in patients with autoimmune diseases (multiple sclerosis or diabetes).