RT Journal Article SR Electronic T1 Clonally distinct differentiation trajectories shape CD8+ memory T cell heterogeneity after acute viral infections in humans JF bioRxiv FD Cold Spring Harbor Laboratory SP 832899 DO 10.1101/832899 A1 Jeff E. Mold A1 Laurent Modolo A1 Joanna Hård A1 Margherita Zamboni A1 Anton J.M. Larsson A1 Carl-Johan Eriksson A1 Patrik L. Ståhl A1 Erik Borgström A1 Simone Picelli A1 Björn Reinius A1 Rickard Sandberg A1 Pedro Réu A1 Carlos Talavera-Lopez A1 Björn Andersson A1 Kim Blom A1 Johan K. Sandberg A1 Franck Picard A1 Jakob Michaëlsson A1 Jonas Frisén YR 2019 UL http://biorxiv.org/content/early/2019/11/08/832899.abstract AB CD8+ T cells play essential roles in immunity to viral and bacterial infections, and to guard against malignant cells. The CD8+ T cell response to an antigen is composed of many T cell clones with unique T cell receptors, together forming a heterogenous repertoire of phenotypically and functionally distinct effector and memory cells1, 2. How individual T cell clones contribute to this heterogeneity during an immune response is key to understand immunity but remains largely unknown. Here, we longitudinally tracked CD8+ T cell clones expanding in response to yellow fever virus vaccination at the single cell level in humans. We show that only a fraction of the clones detected in the acute response persists as circulating memory T cells, indicative of clonal selection. Clones persisting in the memory phase displayed biased differentiation trajectories along a gradient of stem cell memory (SCM) towards terminally differentiated effector memory (EMRA) fates. Reactivation of single memory CD8+ T cells revealed that they were poised to recapitulate skewed differentiation trajectories in secondary responses, and this was generalizable across individuals for both yellow fever and influenza virus. Together, we show that the sum of distinct clonal differentiation repertoires results in the multifaceted T cell response to acute viral infections in humans.