Antigen dependency delineates memory and exhausted CD8 T cells 4050

Abstract Description Antigen experienced T cell subsets are heterogenous, and can be described based on their phenotype, function, and migration properties. Whether antigen stimulation regulates the migration, survival, differentiation, or developmental plasticity of T cell subsets remains unclear. Therefore, we developed a new mouse model that allows dissection between antigen stimulation dynamics and the trajectories of T cell differentiation and maintenance. Specifically, we engineered a novel tamoxifen-inducible TCR-knockout transgenic mouse using a rAAV6 vector encoding for the floxed P14 TCR gene, which allows for the in vivo excision of TCR on a specific fraction of tumor-, acute virus-, or chronic virus-specific T cells. After acute infection with LCMV Armstrong, elimination of the TCR in the effector phase affected the T cell phenotype, promoting differentiation of memory precursor effector cells. Established memory T cells survived without a TCR with no discernable change in phenotype, showing that steady-state memory programs are remarkably TCR-independent, including among resident memory T cells. TCR deletion during chronic infection (30 days after LCMV Clone 13) or cancer caused most cells to die, affecting both the population structure and phenotype. Based on these results, we propose that memory and exhausted T cells can be delineated based on their antigen dependence for survival. Funding Sources JK is supported through the Walter Benjamin-Fellowship of the German Research Foundation (DFG) Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)