Iterative stimulation generates exhaustion resistant T cells 3147

Description It is currently unclear whether T cell exhaustion can be avoided or is an axiomatic product of chronic antigen stimulation. Recently we have demonstrated that memory CD8 T cells are capable of mounting highly functional antigen-dependent responses for more than a decade in vivo, the equivalent of approximately four mouse lifespans. These multi-lifetime cells progressively express exhaustion-related inhibitory proteins yet preserve their proliferative and effector capacities when challenged. To test whether these multi-lifetime iteratively stimulated T cells (ISTCs) were still vulnerable to exhaustion, like other T cells, we subjected them to an in vivo model of chronic antigen exposure. Unexpectedly, these cells resisted exhaustion for far longer than naïve and tertiary memory cells. Throughout this time course, we uncovered changes in a wide range of protein parameters and generated a longitudinal single cell RNA sequencing dataset with the goal of identifying an exhaustion-resistant expression profile in ISTCs. Our results indicate that T cells can adopt exhaustion resistance mechanisms that allow for preserved functionality in the context of persistent antigen. We are currently investigating the precise mechanisms of this through deeper analysis of cell cycle regulation and metabolic programming in these cells and generating genetically modified ISTCs to understand how the deletion of exhaustion-associated proteins may impact their survival in our model.