A selective LIS1 requirement for mitotic spindle assembly discriminates distinct T-cell division mechanisms within the T-cell lineage

Elife. 2022 Dec 15:11:e80277. doi: 10.7554/eLife.80277.

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 β-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.

Keywords: CD4+ T cells; LIS1; T-cell development; cell biology; cell proliferation; immunology; inflammation; mitosis; mouse.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Alkyl-2-acetylglycerophosphocholine Esterase*
  • Animals
  • Cell Lineage
  • Centrosome / metabolism
  • Chromosome Segregation
  • Dyneins / metabolism
  • Mice
  • Microtubule-Associated Proteins* / metabolism
  • Microtubules / metabolism
  • Mitosis
  • Spindle Apparatus / metabolism
  • T-Lymphocytes*

Substances

  • Dyneins
  • Microtubule-Associated Proteins
  • Pafah1b1 protein, mouse
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase

Grants and funding

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.