An early precursor CD8 T cell that adapts to acute or chronic viral infection [scRNA-seq]

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 play a key role in PD-1 directed immunotherapy. These PD-1+ TCF-1+ TOX+ stem-like CD8+ T cells, also referred to as precursors of exhausted T cells, have a distinct program that allows them to adapt to chronic antigen stimulation. Using the mouse model of chronic LCMV infection we found 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 infection outcome. Indeed, we found that nearly identical populations of stem-like CD8+ T cells were generated early after acute or chronic LCMV infection and that antigen was essential for maintaining the stem-like phenotype. We next performed reciprocal adoptive transfer experiments to determine the fate of these early stem-like CD8+ T cells after viral clearance versus persistence. Following transfer of day 5 stem-like CD8+ T cells from chronically infected 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 chronic viral infection. Most importantly, our study shows that the host is prepared a priori to deal with a potential chronic infection. Samples 1-2: Endogenous, LCMV-specific GP33+ CD8+ T cells from days 5 or >45 after chronic LCMV infection. Samples 3-4: LCMV-specific GP33+ P14 Stem-like, TCF7-YFP+ Tim-3-) were sorted from LCMV Armstrong infected mice on day 5 and were transferred into day 5 chronic LCMV infected mice. On day 15 post-transfer, stem-like donor P14 cells as well as endogenous GP33+ from the same recipient mice were isolated from the spleen and analyzed via scRNA-seq.