Grant: Doctoral: Vanier Canada Graduate Scholarships

During infection, immune cells recognize pieces of the infectious organism. When recognition occurs, the cell must alert its processing centre - the nucleus. For this, the message is passed down a chain of molecules, like a series of dominos falling, until it reaches the nucleus. Once in the nucleus, the signal tells the cell to make chemical messengers, called cytokines, that kill the infectious organism and warn other cells. When the infection is resolved, the cell turns the signal off so it doesn't over-react and become exhausted or harm the host. In AIDS and other chronic diseases, the infection is persistent, so immune cells are constantly receiving the 'on' signal. This causes the immune cells to become exhausted, meaning they lose the ability to multiply and make cytokines, leading to impaired infection control. Several molecules are displayed on the surface of exhausted cells, one of which is LAG-3. Somehow, LAG-3 prevents some of the 'on' signal from reaching the nucleus. We think it may do this by blocking the signal from transferring from one step of the pathway to the next. Using the domino analogy, we think that LAG-3 holds up a domino in the pathway, preventing the rest from falling and thereby preventing the signal from reaching the end (the nucleus). Our goal is to discover which step in the pathway LAG-3 blocks by using fluorescent molecules that can tell us whether a molecule has received the 'on' signal (whether the domino has fallen). The first step of the pathway that has not received the 'on' signal (i.e., the first domino still standing) must be where LAG-3 blocks the pathway. In AIDS, cancer and other chronic disease, the immune system must be strong to heal the body. Already, drugs that block LAG-3 are being tested to reverse exhaustion and boost immunity in cancer, even though the way LAG-3 functions is unknown. Our study will help us understand how LAG-3 blocks immune signals and may provide a new drug target to reverse the effect.