A selective LIS1 requirement for mitotic spindle assembly discriminates distinct T-cell division mechanisms within the T-cell lineage
- Inserm, France
Abstract
The ability to proliferate is a common feature of most T-cell populations. However, proliferation follows different cell-cycle dynamics and is coupled to different functional outcomes according to T-cell subsets. Whether the mitotic machineries supporting these qualitatively distinct proliferative responses are identical remains unknown. Here, we show that disruption of the microtubule-associated protein LIS1 in mouse models leads to proliferative defects associated with a blockade of T-cell development after b-selection and of peripheral CD4+ T cell expansion after antigen priming. In contrast, cell divisions in CD8+ T cells occurred independently of LIS1 following T-cell antigen receptor stimulation, although LIS1 was required for proliferation elicited by pharmacological activation. In thymocytes and CD4+ T cells, LIS1-deficiency did not affect signaling events leading to activation but led to an interruption of proliferation after the initial round of division and to p53-induced cell death. Proliferative defects resulted from a mitotic failure, characterized by the presence of extra-centrosomes and the formation of multipolar spindles, causing abnormal chromosomes congression during metaphase and separation during telophase. LIS1 was required to stabilize dynein/dynactin complexes, which promote chromosome attachment to mitotic spindles and ensure centrosome integrity. Together, these results suggest that proliferative responses are supported by distinct mitotic machineries across T-cell subsets.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting file have been provided for Figures 1 and 3.
Article and author information
Author details
Funding
The French ministry of higher education and reserach (PhD fellowship)
- Jérémy Argenty
- Suzanne Mélique
Association pour la recherche sur la Sclérose en Plaques
- Renaud Lesourne
Agence Nationale de la Recherche (ANR-20-CE15-0002)
- Renaud Lesourne
Association pour la Recherche sur le Cancer
- Renaud Lesourne
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Sarah Russell, Peter MacCallum Cancer Centre, Australia
Ethics
Animal experimentation: All the experiments were conducted at the INSERM animal facility (US-006; accreditation number A-31 55508 delivered by the French Ministry of Agriculture to perform experiments on live mice). All experimental protocols were approved by a Ministry-approved ethics committee (CEEA-122) and follow the French and European regulations on care and protection of the Laboratory Animals (EC Directive 2010/63).
Version history
- Received: May 13, 2022
- Preprint posted: May 25, 2022 (view preprint)
- Accepted: December 11, 2022
- Accepted Manuscript published: December 15, 2022 (version 1)
- Version of Record published: December 28, 2022 (version 2)
Copyright
© 2022, Argenty 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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A selective LIS1 requirement for mitotic spindle assembly discriminates distinct T-cell division mechanisms within the T-cell lineage
eLife 11:e80277.
https://doi.org/10.7554/eLife.80277
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