The human CD8 T stem cell-like memory phenotype appears in the acute phase in Yellow Fever virus vaccination

Long-term memory is a fundamental feature of cytotoxic CD8 T cell immunity. Yet when do memory cells arise, especially in humans, is poorly documented, the pathways of effector / memory cell differentiation being largely debated. Based on a cross-sectional study, we previously reported that the live-attenuated Yellow Fever virus vaccine YF-17D induces a stem cell-like memory (SCM) CD8 T cell population persisting for at least 25 years. Here we present longitudinal data revealing that an activated SCM phenotype is distinctly detectable early on following YF-17D vaccination, i.e. at the same time as activated effector cells. In the long-run, the cells that express the transcription factor T cell factor 1 (TCF1) preferentially persist, consistent with the role of TCF1 in memory establishment. By performing t-distributed Stochastic Neighbour Embedding of flow cytometry data on standard differentiation and activation markers, we obtained a time-lapse representation of the dynamics of the CD8 T cell response: SCM cells appear early and remain closely related to the baseline Naive cells, while effector cells burst out of baseline and gradually contract after the peak of the response. Altogether, we observe heterogeneity in differentiation phenotypes in both the acute phase and the decade-long-term phases, including cells with memory phenotypes very early in the response. As opposed to models where memory cells develop from effector cells, our data support differentiation models where long-term memory cells are established by the early decision to retain proximity to the Naive state in a memory-dedicated pool of cells.