TY - JOUR T1 - Clonally distinct differentiation trajectories shape CD8<sup>+</sup> memory T cell heterogeneity after acute viral infections in humans JF - bioRxiv DO - 10.1101/832899 SP - 832899 AU - Jeff E. Mold AU - Laurent Modolo AU - Joanna Hård AU - Margherita Zamboni AU - Anton J.M. Larsson AU - Carl-Johan Eriksson AU - Patrik L. Ståhl AU - Erik Borgström AU - Simone Picelli AU - Björn Reinius AU - Rickard Sandberg AU - Pedro Réu AU - Carlos Talavera-Lopez AU - Björn Andersson AU - Kim Blom AU - Johan K. Sandberg AU - Franck Picard AU - Jakob Michaëlsson AU - Jonas Frisén Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/11/08/832899.abstract N2 - 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. ER -