Identification of two transitional stem-like memory CD8+ T cell states during viral infection and vaccination

Stem-like CD8+ T cells are a key feature of chronic conditions and long-lived memory. Currently stem-like CD8+ T cells are named according to their environment, where precursors of exhausted (TPEX) cells arise in chronic viral infections, autoimmunity and cancer, while stem cell-like memory (TSCM) cells are associated with acute infection and vaccination. Here, we established and validated a method to monitor the transition between transcriptionally distinct TPEX and TSCM cell states. We reveal a linear and reversible developmental trajectory that is concomitant with viral clearance. Further, we demonstrate that TPEX to TSCM cell conversion is observed during acute viral infection and vaccination, aligning the processes that establish stem-like CD8+ T cells in acute and chronic settings. This work supports the potential to monitor stem-like CD8+ T cell conversion as biomarkers of disease in patients with chronic infection, cancer, and autoimmunity and broadens the importance of this transition during the establishment of vaccine-induced long-lived immune protection. Paired single cell RNA sequencing (scRNAseq) and surface protein sequencing (CITEseq) analysis compared P14 cells from day 8 acute LCMV Armstrong infection (4499 cells) and chronic LCMV Docile infection (4967 cells) with days 0-1 IFNAR blocked LCMV Armstrong at both day 8 (5061 cells) and day 14 (3102 cells).