Project 171268

During an encounter with a foreign pathogen such as a virus or bacterium, the immune system responds by generating a large number of specialized "T cells" to seek and destroy the invading pathogen. When the infectious microbe is eliminated the majority of T cells undergo cell death and this contraction is a means to restore normal T cell homeostasis. However, a small proportion of T cells are able survive and transform into distinct cells termed memory T cells. The end product of this process is the generation of "immunological memory" and represents the foundation to life-long immunity to the pathogen. One important but unresolved question is how are these memory T cells maintained for the lifespan of the host? This is an essential consideration because the generation of memory T cells is the basis for our success in all human vaccinations and a major goal in developing vaccines for diseases such as HIV/AIDS and cancer. Based on initial laboratory experiments, we have uncovered a process called autophagy which is involved in promoting cell survival when cells are exposed to low oxygen. Our results also demonstrate that memory T cells exhibit features that are characteristic of autophagy. Therefore, the proposed research will use a well established lymphocytic choriomeningitis virus (LCMV) model to investigate how T cells survive this pathogenic infection, and ultimately develop long-term immunity. In Aim 1, we will use immunological and genetic approaches to test whether autophagy is necessary for the development of memory T cells during LCMV infection. In Aim 2, we will define how low oxygen can activate the autophagy survival pathway. This information can be used in the future to provide molecular insight into survival of other types of long-lived cells such as cancer stem cells and to design immune-based treatments to destroy these cells.

using the LCMV virus model to investigate the role of autophagy in memory T cell development and survival, particularly in hypoxic conditions