A selective LIS1 requirement for mitotic spindle assembly discriminates distinct T-cell division mechanisms within the T-cell lineage
Jérémy Argenty, Nelly Rouquié, Cyrielle Bories, Suzanne Mélique, Valérie Duplan-Eche, Abdelhadi Saoudi, Nicolas Fazilleau, Renaud Lesourne.
elife 2022, Dec 15;11:e80277. doi: 10.7554/eLife.80277
T cells develop in the thymus from progenitor cells so called thymocytes. During their development, T cells acquire a functional T-cell receptor (TCR), which recognize pathogens fragments (antigens) associated to histocompatibility molecules (MHC). T-cell progenitors differentiate into two major subsets, CD4+ helper T cells, which regulate the biological functions of other immune cells, and CD8+ T cells, which kill cells infected by intracellular pathogens. One common characteristic of these different T-cell subsets is their ability to proliferate in response to TCR stimulation by peptide-MHC complexes. Cell division enables primarily T-cell expansion but it is also coupled to different outcomes such as differentiation into mature thymocytes or acquisition of distinct effector functions in CD4+ and CD8+ T cells. Whether the mitotic machinery supporting these qualitatively distinct proliferative responses are identical is unknown.
A publication in eLife (doi: 10.7554/eLife.80277) by the group of Renaud Lesourne show that disruption of the microtubule-associated protein LIS1 in mouse models leads to proliferative defects of thymocytes at early stages of T-cell development and of peripheral CD4+ T-cell after antigen priming. In contrast, cell divisions in CD8+ T cells occurred independently of LIS1 following TCR stimulation. In thymocytes and CD4+ T cells, proliferative defects resulted from a mitotic failure, characterized by the presence of extra-centrosomes and the formation of multipolar spindles, causing abnormal chromosomes distribution during metaphase and telophase, aneuploidy and tumor suppressive programs. LIS1 was required to stabilize dynein/dynactin complexes, which promote chromosome attachment to mitotic spindles and ensure centrosome integrity.
These results suggest that distinct molecular mechanisms discriminate mitoses across T cell subsets to adequately couple cell divisions and differentiation outcomes. They also suggest that T-cell proliferation could be targeted in a selective manner to prevent the deleterious expansion of specific T-cell subsets in contexts such as cancer and autoimmunity.