Cellular and molecular mechanisms of inflammatory T cell regulation.

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T cells of the immune system proliferate rapidly in response to bacteria, viruses and tumors. They co-ordinate the body's response to pathogens and cancer by either killing infected cells directly, or by attracting other accessory immune cells to promote inflammation. As T cells can multiply at a dramatic rate in response to infection, and as they produce many antimicrobial and antiviral molecules that can be toxic to the body in large amounts, it is crucial that T cell responses be tightly controlled. T cells thus express negative signaling receptors on their surface. Triggering of negative surface receptors leads to the activation of protein signaling pathways within the T cell, causing them to either die or to reduce their pro-inflammatory functions. In this way, the immune system avoids excessive, inappropriate inflammation once an infection has been cleared.  The main goal of this research program is to identify molecular pathways downstream of negative signaling receptors. We have previously identified a molecule, Bat3, that stops signaling via the negative receptor Tim-3. Bat3 thus promotes T cell-driven inflammation. However, there is much that we still need to learn about the function of Bat3 in T cells. Using a combination of molecular and cell biological approaches, my team and I will define the molecular pathways by which Bat3 operates. We will then identify other T cell proteins that bind to Bat3 and that affect these pathways. We will then use cutting edge technology to determine how specific T cell growth factors can influence the strength of binding of Bat3 to other molecules in living cells. Taken together, this NSERC program will allow us to better understand the molecular signals that mediate negative regulation of T cell responses. The findings will have direct implications for future studies aimed at creating a molecular map of protein interactions that are relevant to maintaining proper function of the immune system. This NSERC program will also ensure the training of future highly qualified students, postdoctoral fellows and research assistants in techniques relevant to fundamental research.**