Jonathan D. Powell, MD, PhD
The 2 signal model provides the framework for our understanding of T cell responses. Using high throughput microarray analysis we have uncovered several novel TCR-induced genes and pathways that play critical roles in dictating the outcome of antigen recognition. We identified Egr-2 and Egr-3 as playing an important role in determining the fate of TCR recognition (Signal 1). Egr-2 and Egr-3 null T cells induce more aggressive autoimmune disease but are more effective in mounting anti-tumor responses. A second gene that was revealed by our screen is the adenosine A2aR. Activating the receptor can promote tolerance and inhibit autoimmune disease. Alternatively employing A2aR null mice and specific antagonists promotes anti-tumor immunity and enhances vaccine responses. In addition to Signal 1, we are also interested in understanding mechanisms of costimulation. Along these lines we have identified the mammalian Target of Rapamycin (mTOR) as playing a central role in dictating the outcome of antigen recognition. By engineering mice to delete mTOR in T cells we have determined that mTOR is critical for Th1, Th2 and Th17 differentiation. Furthermore, in the absence of mTOR T cells differentiate down a Foxp3+ regulatory T cell pathway. Currently, we are using T cell specific Rheb, Rictor and TSC2 null mice in order to dissect the upstream and downstream signaling pathways responsible for regulating T cells. In addition, by taking a proteomic approach we are seeking to identify novel substrates specifically involved in dictating mTOR-induced T cell differentiation.