Formation and fate of stem-cell like Tcf7+ CD8+ T cells during a primary immune response to viral infection [ATAC-seq]

In response to infection, naïve CD8+ T cells (Tn) expand and differentiate into short-lived terminal effector (Tte) cells, which eliminate infected cells, or into central memory (Tcm) cells, which persist following pathogen clearance and mediate protection against re-infection thanks to their stem cell-like properties. The stage-specific signals required for the cell fate changes have remained incompletely understood. Here we find that Tn cells, which express the transcription factor Tcf1 (Tcf7), yield Tcf1+ cells, which retain stem-like potential throughout the primary response and which quantitatively yield Tcf1+ Tcm cells following pathogen clearance. However, only the Tcf1+ cells present during priming are competent to yield Tcf1- Tte cells. Priming commits cells to undergo multiple divisions while maintaining Tcf1 expression. The presence of type I interferon during the division, rather than the priming phase suppresses Tcf1 expression. Tcf1 loss results in the stable loss of stemness, an event that precedes the stable acquisition of a Tte state. Thus, inflammatory cytokines drive Tte differentiation from dividing Tcf1+ cells, which are prone to become Tcm cells. Overall design: Tcf7GFP P14 cells (CD45.2) purified from the spleen of naive mice were adoptively transferred into C57BL/6 (B6) mice (CD45.1) one day prior to infection with LCMV Armstrong (Arm). At d4 and d8 post infection, Tcf7GFP+, Tcf7GFP- Klrg1- and Tcf7GFP- Klrg1+ P14 cells were flow sorted from the spleens of infected recipient mice. CD8+ CD44- CD62L+ cells were flow sorted from the spleen of naive P14 mice (d0). The sorted cells were subjected to bulk ATACseq analysis.