This study examines the origin and differentiation of stem-like CD8+ T cells that are essential for sustained T cell immunity in chronic viral infections and cancer and also have a key role in PD-1 directed immunotherapy1–10. These PD-1+TCF-1+TOX+ stem-like CD8+ T cells (also known as precursors of exhausted T cells8,9) have a distinct program that enables them to adapt to chronic antigen stimulation. Here, using the mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection, we find that virus-specific stem-like CD8+ T cells are generated early (day 5) during chronic infection, suggesting that this crucial fate commitment occurs irrespective of the infection outcome. Indeed, we find that nearly identical populations of stem-like CD8+ T cells were generated early during acute or chronic LCMV infection, and that antigen was essential for maintaining the stem-like phenotype. We performed reciprocal adoptive transfer experiments to determine the fate of these early stem-like CD8+ T cells after viral clearance versus persistence. After transfer of day 5 stem-like CD8+ T cells from chronically infected mice into acutely infected mice, these cells downregulated canonical markers of the chronic stem-like CD8+ T cells and expressed markers (CD127 and CD62L) associated with central memory CD8+ T cells. Reciprocally, when day 5 stem-like cells from acutely infected mice were transferred into chronically infected mice, these CD8+ T cells functioned like chronic resource cells and responded effectively to PD-1 therapy. These findings highlight the ability of these early PD-1+TCF-1+TOX+ stem-like CD8+ T cells to adapt their differentiation trajectory to either an acute or a chronic viral infection. Importantly, our study shows that the host is prepared a priori to deal with a potential chronic infection.
