Grant: Operating Grant

When a host becomes infected with a virus or bacteria the immune system responds by generating a large number of immune "T cells" to seek and destroy the microorganism. This expansion in cells can be in excess of ten fold so that adequate T cells can neutralize the infection. When the infection is eliminated most T cells die so that normal numbers of circulating T cells are restored. However, a small proportion of T cells do not die but instead survive and transform into "memory T cells". Memory T cells go on to survive for the lifetime of the host so that a second infection with the same microorganism leads to stronger immunity. In this way, the host develops "memory" to the infectious agent. This is one of the most basic aspects of the immune system and is the principle on which the development of every successful human vaccine is based. Despite this achievement, we do not fully understand how memory T cells survive for the entire lifespan of the host which in the case of humans can be greater than 60 years. Based on our initial experiments, we have found that memory T cells turn on a survival program called "autophagy". We believe that this distinct form of survival is necessary for the generation and maintenance of memory T cells. We also have evidence to suggest that autophagy is switched on when memory cells are exposed to low levels of key metabolites. In this proposal, we will: 1) determine whether autophagy is required for memory T cell development, and 2) determine what factors activate memory T cell autophagy and how this is accomplished at the molecular level. This information can be used to understand how other cell types including rare long-lived cancer stem cells that may be responsible for the development of primary as well as recurrent tumors, are endowed with this survival property. The answers to these questions may enable us to exploit this property to develop more effective treatments for diseases such as HIV/AIDS and cancer.