Emergence and fate of stem cell-like Tcf7⁺ CD8⁺ T cells during a primary immune response to viral infection

In response to infection, naive CD8(+) T (T-N) cells yield a large pool of short-lived terminal effector (T-TE) cells that eliminate infected host cells. In parallel, a minor population of stem cell-like central memory (T-CM) cells forms, which has the capacity to maintain immunity after pathogen clearance. It has remained uncertain whether stem-like T-CM cells arise by dedifferentiation from a subset of cytolytic T-TE cells or whether priming generates stem-like cells capable of seeding the T-CM compartment and, if so, when cytolytic T-TE cells branch off. Here, we show that CD8(+) T cells with stem-like properties, which are identified by the expression of TCF1 (encoded by Tcf7), are present across the primary response to infection. Priming programs T-N cells to undergo multiple cell divisions, over the course of which TCF1 expression is maintained. These TCF1(+) cells further expand relatively independently of systemic inflammation, antigen dose, or affinity, and they quantitatively yield TCF1(+) T-CM cells after pathogen clearance. Inflammatory signals suppress TCF1 expression in early divided TCF1(+) cells. TCF1 down-regulation is associated with the irreversible loss of self-renewal capacity and the silencing of stem/memory genes, which precedes the stable acquisition of a T-TE state. TCF1 expression restrains cell cycling, explaining in part the limited expansion of TCF1(+) relative to TCF1(-) cells during the primary response. Thus, our data are consistent with terminal differentiation of effector cells being a step-wise process that is initiated by inflammation in primed stem-like cells, which would otherwise become central memory cells by default.