Keywords: T cells, tolerance, mTOR , cancer immunotherapy.
Our laboratory is interested in understanding the biochemical and molecular pathways that govern T cell activation versus tolerance…..
The 2 signal model provides the framework for our understanding of T cell responses. Signal 1 refers to T Cell Receptor (TCR) recognition while Signal 2 refers to engagement of costimulatory receptors by ligands present on activated antigen presenting cells. 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 the Early Growth Response (EGR) family of transcription factors as playing an important role in determining the fate of TCR recognition. Indeed, Egr-2 and Egr-3 null T cells induce more aggressive autoimmune disease but also are more effective in mounting anti-tumor responses. A second pathway that was revealed by our screen involves activation of the adenosine A2aR. Activating the receptor with A2aR agonists can promote tolerance and inhibit autoimmune disease. Alternatively, by employing A2aR null mice and specific antagonists, the lab is interested in blocking the ability to tumor-derived adenosine to inhibit T cell function and thus enhance the efficacy to tumor vaccines.
In addition to Signal 1, we are also interested in understanding how accessory signals derived from the environment (Signal 2) regulate T cell activation and function. Along these lines we have identified the evolutionarily conserved Serine/Threonine kinase 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 activation 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 engineering 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.
Profile: Publications and Interests