Early Generation and Anatomical Commitment of Stem-like CD8 T cells

Abstract Stem-like CD8 T cells sustain the CD8 T cell response during chronic viral infection and cancer, and residency in lymphoid tissues is a key aspect of their biology. We used the chronic LCMV strain, clone 13, to determine when these cells first emerge and commit to positioning in lymphoid sites. Phenotypical and transcriptional profiling of virus-specific CD8 T cells indicated that stem-like and effector fates diverge as early as day 5 after infection. PD-1+ stem-like CD8 T cells sorted from the early (day 5) and established phases (>day 45) of clone 13 infection showed substantial transcriptional overlap indicating that the canonical gene signature of these cells manifests early and is maintained throughout infection. Intravascular labeling and imaging showed that the spatial commitment of these cells to the splenic white pulp also began on day 5. These observations were striking as stem-like CD8 T cells are considered an adaptation to prolonged antigen exposure, yet their fate and anatomical commitments are made before the trajectory of infection is clearly acute or chronic. There were important time-related changes to these cells as well. Early stem-like cells were proliferating and expressed genes involved in the cell cycle, mTOR signaling, and anabolic metabolism. As infection progressed, they upregulated multiple inhibitory molecules and eventually became quiescent. Thus, the stem-like transcriptional and anatomical commitment occurs very early after infection. These data indicate that the CD8 T cell response is equipped for chronic antigen exposure before the trajectory of infection is clearly acute or chronic and further highlight the importance of location for stem-like CD8 T cells. Supported by grants from NIH (5R01AI030048-29)