Divergent clonal differentiation trajectories establish CD8+ memory T cell heterogeneity during acute viral infections in humans

The CD8+ T cell response to an antigen is composed of many T cell clones with unique T cell receptors, together forming a heterogeneous repertoire of effector and memory cells. How individual T cell clones contribute to this heterogeneity throughout immune responses remains largely unknown. In this study, we longitudinally track human CD8+ T cell clones expanding in response to yellow fever virus (YFV) vaccination at the single-cell level. We observed a drop in clonal diversity in blood from the acute to memory phase, suggesting that clonal selection shapes the circulating memory repertoire. Clones in the memory phase display biased differentiation trajectories along a gradient from stem cell to terminally differentiated effector memory fates. In secondary responses, YFV- and influenza-specific CD8+ T cell clones are poised to recapitulate skewed differentiation trajectories. Collectively, we show that the sum of distinct clonal phenotypes results in the multifaceted human T cell response to acute viral infections. [Display omitted] •Decrease in human CD8+ T cell clonal diversity from acute to memory phase•Clonally biased differentiation trajectories of CD8+ T cells in primary responses•Clonally skewed CD8+ memory T cell differentiation in secondary recall responses Mold et al. investigate the clonal architecture of the human CD8+ T cell response to vaccination with live attenuated yellow fever virus, and they demonstrate that the multifaceted T cell response to an acute viral infection is created by the sum of distinct clonal phenotypes.