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Clonally distinct differentiation trajectories shape CD8+ memory T cell heterogeneity after acute viral infections in humans

View ORCID ProfileJeff E. Mold, View ORCID ProfileLaurent Modolo, View ORCID ProfileJoanna Hård, View ORCID ProfileMargherita Zamboni, View ORCID ProfileAnton J.M. Larsson, Carl-Johan Eriksson, View ORCID ProfilePatrik L. Ståhl, View ORCID ProfileErik Borgström, Simone Picelli, View ORCID ProfileBjörn Reinius, View ORCID ProfileRickard Sandberg, Pedro Réu, View ORCID ProfileCarlos Talavera-Lopez, View ORCID ProfileBjörn Andersson, Kim Blom, Johan K. Sandberg, Franck Picard, View ORCID ProfileJakob Michaëlsson, View ORCID ProfileJonas Frisén
doi: https://doi.org/10.1101/832899
Jeff E. Mold
1Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden
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Laurent Modolo
2LBBE, UMR CNRS 5558, Université Lyon 1, Villeurbanne, France LBMC UMR 5239 CNRS/ENS Lyon, Lyon, France
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Joanna Hård
1Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden
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Margherita Zamboni
1Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden
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  • ORCID record for Margherita Zamboni
Anton J.M. Larsson
1Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden
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Carl-Johan Eriksson
1Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden
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Patrik L. Ståhl
1Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden
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Erik Borgström
4Science for Life Laboratory, Division of Gene Technology, KTH Royal Institute of Technology, SE-106 91 Stockholm, Sweden
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  • ORCID record for Erik Borgström
Simone Picelli
1Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden
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Björn Reinius
1Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden
5Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden
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Rickard Sandberg
1Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden
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Pedro Réu
1Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden
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Carlos Talavera-Lopez
1Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden
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Björn Andersson
1Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden
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Kim Blom
3Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden
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Johan K. Sandberg
3Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden
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Franck Picard
2LBBE, UMR CNRS 5558, Université Lyon 1, Villeurbanne, France LBMC UMR 5239 CNRS/ENS Lyon, Lyon, France
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Jakob Michaëlsson
3Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden
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  • For correspondence: jonas.frisen@ki.se jakob.michaelsson@ki.se
Jonas Frisén
1Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden
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  • ORCID record for Jonas Frisén
  • For correspondence: jonas.frisen@ki.se jakob.michaelsson@ki.se
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Abstract

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.

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Clonally distinct differentiation trajectories shape CD8+ memory T cell heterogeneity after acute viral infections in humans
Jeff E. Mold, Laurent Modolo, Joanna Hård, Margherita Zamboni, Anton J.M. Larsson, Carl-Johan Eriksson, Patrik L. Ståhl, Erik Borgström, Simone Picelli, Björn Reinius, Rickard Sandberg, Pedro Réu, Carlos Talavera-Lopez, Björn Andersson, Kim Blom, Johan K. Sandberg, Franck Picard, Jakob Michaëlsson, Jonas Frisén
bioRxiv 832899; doi: https://doi.org/10.1101/832899
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Clonally distinct differentiation trajectories shape CD8+ memory T cell heterogeneity after acute viral infections in humans
Jeff E. Mold, Laurent Modolo, Joanna Hård, Margherita Zamboni, Anton J.M. Larsson, Carl-Johan Eriksson, Patrik L. Ståhl, Erik Borgström, Simone Picelli, Björn Reinius, Rickard Sandberg, Pedro Réu, Carlos Talavera-Lopez, Björn Andersson, Kim Blom, Johan K. Sandberg, Franck Picard, Jakob Michaëlsson, Jonas Frisén
bioRxiv 832899; doi: https://doi.org/10.1101/832899

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