Formation and fate of stem-cell like Tcf7+ CD8+ T cells during a primary immune response to viral infection [scRNA-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). Total P14 cells sorted from the spleen of recipient mice at d2, d3, d4 and d6 post infection (p.i) or from the spleen of naive mice (d0), were subjected to scRNA-Seq analysis.