Stochastic asymmetric repartition of lytic machinery in dividing CD8+ T cells generates heterogeneous killing behavior
- Centre de Recherche en Cancérologie de Toulouse, France
- Toulouse School of Economics, UMR 5604, France
- Centre de Physiopathologie de Toulouse Purpan, France
Abstract
Cytotoxic immune cells are endowed with a high degree of heterogeneity in their lytic function, but how this heterogeneity is generated is still an open question. We therefore investigated if human CD8+ T cells could segregate their lytic components during telophase, using imaging flow cytometry, confocal microscopy and live cell imaging. We show that CD107a+-intracellular vesicles, perforin and granzyme B unevenly segregate in a constant fraction of telophasic cells during each division round. Mathematical modeling posits that unequal lytic molecule inheritance by daughter cells results from the random distribution of lytic granules on the two sides of the cleavage furrow. Finally, we establish that the level of lytic compartment in individual CTL dictates CTL killing capacity. Together, our results show the stochastic asymmetric distribution of effector molecules in dividing CD8+ T cells. They propose uneven mitotic repartition of pre-packaged lytic components as a mechanism generating non-hereditary functional heterogeneity in CTL.
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All data generated or analysed during this study are included in the manuscript and supporting files.
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Funding
Laboratoire d'Excellence Toulouse Cancer (ANR11-LABEX)
- Salvatore Valitutti
Region occitanie (RCLE R14007BB,671 34 No 12052802,and RBIO R15070BB,No 14054342)
- Salvatore Valitutti
Fondation Toulouse Cancer Santé (2014CS044)
- Salvatore Valitutti
Ligue Contre le Cancer (équipe labellisée)
- Salvatore Valitutti
Ligue Contre le Cancer (4th year phD)
- Romain Jugele
Bristol-Myers Squibb (No CA184-575)
- Salvatore Valitutti
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: Buffy coats of healthy donors were obtained through the Etablissement Français du Sang (EFS, Toulouse, France). Blood samples were collected and processed following standard ethical procedures (Helsinki 433 protocol), after obtaining written informed consent from each donor and approval by the French Ministry of the Research (transfer agreement AC-2014-2384). Approbation by the ethical department of the French Ministry of the Research for the preparation and conservation of cell lines and clones starting from healthy donor human blood samples has been obtained (authorization No DC-2018-3223).
Copyright
© 2021, Lafouresse et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Stochastic asymmetric repartition of lytic machinery in dividing CD8+ T cells generates heterogeneous killing behavior
eLife 10:e62691.
https://doi.org/10.7554/eLife.62691
