Grant: Project Grant

CD8 cytotoxic T lymphocytes (CTLs) provide major protection against infection and cancer. Upon infection, CTLs undergo a three-phase developmental program, wherein they first rapidly proliferate in the expansion phase and differentiate into effectors that kill infected cells. Then, the majority (~90-95%) of CTLs die by apoptosis in the contraction phase, and the remaining surviving cells (~5-10%) become long-term memory CTLs in the memory phase. However, what mechanism determines CTL die or survival remains unresolved. Since the goal of vaccination is to prevent diseases by immunological memory, a detailed understanding of the molecular basis for CTL fate and memory is critical to vaccine design. T cell-surface mannose-6-phosphate receptor (M6PR) is a multifunctional receptor that can uptake cytolytic molecule called granzyme-B (GzmB), leading to T cell death. We demonstrated that CTLs with low M6PR -expression (M6PRlow-CTLs) survived because GzmB could not bind to and kill these M6PRlow-CTLs. We also demonstrated that interleukin (IL)-7 cytokine was able to down-regulate CTL M6PR-expression, thus leading to M6PRlow-CTL surviving the contraction phase and becoming memory CTLs. In this project, we will elucidate the molecular mechanisms or pathways regulating T cell fate and memory in IL-7-stimulated CTLs. Therefore, we can incorporate our findings in rational vaccine design to develop potent vaccines with less contraction, but enhanced CTL memory and in new drug development for infectious and cancer diseases.