Mucosal T cell memory to pathogens

Project Summary T cell immunity may be exploited through vaccination, immunomodulating therapies, and engineered adoptive cell therapies to immunize against or control infections and cancer. However repeated or prolonged stimulation can result in T cell dysfunction and senescence which impairs protective immunity or allows disease progression. Establishing numerically robust, durable, and functional T cell immunity and preventing or reversing T cell exhaustion remain substantial goals in immunology that have significant clinical ramifications. Our preliminary data demonstrates that repeated stimulation, even when punctuated by periods of rest, can result in senescence. However, we also show that this fate can be avoided, allowing indefinite boosting across multiple mouse lifetimes, while preserving function and durability. Additional preliminary data indicates that T cells can adapt to become inured to exhaustion. The goals of this proposal are to determine the underlying mechanisms that permit T cells to undergo indefinite clonal expansion while avoiding functional exhaustion or proliferative senescence. Successful execution of the proposal will inform our understanding of the regulation of immunological memory, vaccine development, and immune therapies for chronic diseases. .