Antigen dependency defines memory and exhausted CD8 T cell fates 2257447

Abstract

Antigen experienced T cell subsets are heterogenous, and can be described based on their phenotype, function, and migration properties. We wished to better understand how antigen stimulation regulates the trafficking, survival, differentiation and developmental plasticity of T cell subsets. We developed a new mouse model that allows for the in vivo excision of the P14 TCR on a defined fraction of antigen-specific CD8 T cells. Specifically, we engineered a novel tamoxifen-inducible TCR-knockout transgenic mouse using a rAAV6 vector encoding for the floxed P14 TCR gene. This model allows for permanent cessation of antigen stimulation on select T cells at time points of our choosing. After acute infection with LCMV Armstrong, elimination of the TCR on established memory CD8 T cells maintained stable subset composition, but resulted in detectable downregulation of exhaustion markers, indicating that TCR sensing occurs among steady-state memory T cells. TCR deletion during chronic infections (LCMV Minnesota and LCMV Cl13 ± aCD4 depletion) affected both the population structure and phenotype. Terminal (Tex/TXt), as well as progenitor exhausted (Tpex/TXp) T cell subsets substantially declined after TCR deletion in persistently viremic infection with LCMV Cl13 + aCD4. However, the loss of Tpex/TXp after TCR deletion was moderated in settings of chronic infections without CD4 T cell depletion, in which most host viral load was more tightly controlled. These results demonstrate that the antigen dependence of Tpex/TXp depends on context, and a subset may survive in the absence of further antigen stimulation, which has important implications for maintaining immunity to chronic infections and cancer. Walter Benjamin Program, DFG Lymphocyte Differentiation and Peripheral Maintenance (LYM)