Mold and Modolo et al. longitudinally tracked individual CD8+ T cell clones responding to yellow fever virus (YFV) vaccination to determine the clonal contributions to memory T cell heterogeneity in response to infection. Peripheral YFV-specific CD8+ T cell clonal diversity declined from the acute to the memory phase of the primary antiviral immune response, and trajectory analysis and scRNAseq revealed the emergence of cells with biased TEMRA or TSCM fates, which contributed to the phenotypic heterogeneity in CD8+ T memory repertoires. In secondary responses, clonally distinct effector progeny emerged from CD8+ TEMRA and TSCM founder cells.
Contributed by Shishir Pant
ABSTRACT: 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.