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Article
Ton Schumacher
The Netherlands Cancer Institute
Corresponding Author
ORCiD: https://orcid.org/0000-0003-0517-8804
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Clonal expansion is a core aspect of T cell immunity. However, little is known with respect to the relationship between replicative history and the formation of distinct CD8+ memory T cell subgroups. To address this issue, we developed a genetic-tracing approach, termed the DivisionRecorder, that reports the extent of past proliferation of cell pools in vivo. Using this system to genetically ‘record’ the replicative history of different CD8+ T cell populations throughout a pathogen-specific immune response, we demonstrate that the central memory T cell (TCM) pool is marked by a higher number of prior divisions than the effector memory T cell pool, due to the combination of strong proliferative activity during the acute immune response and selective proliferative activity after pathogen clearance. Furthermore, by combining DivisionRecorder analysis with single cell transcriptomics and functional experiments, we show that replicative history identifies distinct cell pools within the TCM compartment. Specifically, we demonstrate that lowly divided TCM display enriched expression of stem-cell-associated genes, and that such lowly divided cells are superior in eliciting a proliferative recall response. The latter data provide the first evidence that a stem cell like memory T cell pool that reconstitutes the CD8+ T cell effector pool upon reinfection is marked by prior quiescence.
Keywords
Proliferation dynamics, lineage tracing, Probabilistic labeling, Replicative history, T cell memory
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This preprint is under consideration at a Nature Portfolio Journal. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Nature journals have partnered with Research Square to offer In Review, a journal-integrated preprint deposition service.
Article
Ton Schumacher
The Netherlands Cancer Institute
Corresponding Author
ORCiD: https://orcid.org/0000-0003-0517-8804
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version 1
Posted 19 Mar, 2021
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Immunology
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Clonal expansion is a core aspect of T cell immunity. However, little is known with respect to the relationship between replicative history and the formation of distinct CD8+ memory T cell subgroups. To address this issue, we developed a genetic-tracing approach, termed the DivisionRecorder, that reports the extent of past proliferation of cell pools in vivo. Using this system to genetically ‘record’ the replicative history of different CD8+ T cell populations throughout a pathogen-specific immune response, we demonstrate that the central memory T cell (TCM) pool is marked by a higher number of prior divisions than the effector memory T cell pool, due to the combination of strong proliferative activity during the acute immune response and selective proliferative activity after pathogen clearance. Furthermore, by combining DivisionRecorder analysis with single cell transcriptomics and functional experiments, we show that replicative history identifies distinct cell pools within the TCM compartment. Specifically, we demonstrate that lowly divided TCM display enriched expression of stem-cell-associated genes, and that such lowly divided cells are superior in eliciting a proliferative recall response. The latter data provide the first evidence that a stem cell like memory T cell pool that reconstitutes the CD8+ T cell effector pool upon reinfection is marked by prior quiescence.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 6
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