The Microtubule-Associated Protein Lis1 Regulates T Lymphocyte Homeostasis and Differentiation

Ngoi, Soo; Lopez, Justine; Chang, John T.

doi:10.4049/jimmunol.1502410

Cited by 5 publications

(22 citation statements)

References 41 publications

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“…As previously reported in a similar conditional knockout model (34), the deletion of LIS1 led to a dramatic decrease of peripheral CD4+ and CD8+ T cells numbers (Figure 3 – Figure Supplement 1D). This defect was previously imputed to a reduced ability of CD4+ and CD8+ T cells to proliferate in response to cytokine-driven homeostatic signals (34).…”

Section: Resultssupporting

confidence: 85%

“…The maturation of DP thymocytes into TCR hi CD4 SP thymocytes occurred also normally in Cd4-Cre Lis1 flox/flox mice expressing a fixed MHC class II-restricted ab-TCR transgene (AND), suggesting that LIS1 is not essential for positive selection (Figure 3 -Figure Supplement 1C). As previously reported in a similar conditional knockout model (34), the deletion of LIS1 led to a dramatic decrease of peripheral CD4+ and CD8+ T cells numbers (Figure 3 -Figure Supplement 1D).…”

Section: Lis1 Is Required For Tcr-mediated Proliferation In Cd4+ T Ce...supporting

confidence: 85%

“…This defect was previously imputed to a reduced ability of CD4+ and CD8+ T cells to proliferate in response to cytokine-driven homeostatic signals (34).…”

Section: Lis1 Is Required For Tcr-mediated Proliferation In Cd4+ T Ce...mentioning

confidence: 99%

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

Argenty

Rouquié

Bories

et al. 2022

Preprint

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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 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.

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Section: Resultssupporting

confidence: 85%

Section: Lis1 Is Required For Tcr-mediated Proliferation In Cd4+ T Ce...supporting

confidence: 85%

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

Argenty

Rouquié

Bories

et al. 2022

Preprint

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“…The microtubule reassembles and contributes to mitotic spindle formation during cell division. Therefore, as a microtubuleassociated protein, Lis1 is also reported to regulate cell division and expansion (17,18,42). Using sequential EdU-BrdU pulsing, we have definitively demonstrated that Lis1 deficiency led to a GC B cell cycle blockade at the G 2 /M phase.…”

Section: Discussionmentioning

confidence: 75%

Lis1 Regulates Germinal Center B Cell Antigen Acquisition and Affinity Maturation

Chen

Cai

Zhang

et al. 2017

The Journal of Immunology

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The germinal center (GC) is the site where activated B cells undergo rapid expansions, somatic hypermutation, and affinity maturation. Affinity maturation is a process of Ag-driven selection. The amount of Ag acquired and displayed by GC B cells determines whether it can be positively selected, and therefore Ag acquisition has to be tightly regulated to ensure the efficient affinity maturation. Cell expansion provides sufficient quantity of GC B cells and Abs, whereas affinity maturation improves the quality of Abs. In this study, we found that Lis1 is a cell-intrinsic regulator of Ag acquisition capability of GC B cells. Lack of Lis1 resulted in redistribution of polymerized actin and accumulation of F-actin at uropod; larger amounts of Ags were acquired and displayed by GC B cells, which presumably reduced the selection stringency. Affinity maturation was thus compromised in Lis1-deficient mice. Consistently, overexpression of Lis1 in GC B cells led to less Ag acquisition and display. Additionally, Lis1 is required for GC B cell expansion, and Lis1 deficiency blocked the cell cycle at the mitotic phase and GC B cells were prone to apoptosis. Overall, we suggest that Lis1 is required for GC B cell expansion, affinity maturation, and maintaining functional intact GC response, thus ensuring both the quantity and quality of Ab response.

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“…They regulate the polarized secretion of effector molecules and contribute to the maintenance of F-actin-dependent structures (15)(16)(17). Also microtubules are highly plastic and dynamic structures and orchestrated by microtubule-stabilizing and destabilizing proteins including microtubules-associated proteins (MAPs), Lissencephaly 1 (Lis1), stathmin, and tau protein (18)(19)(20). Interesting, Lis1-deficient murine models show a reduction in the number of both CD4 + and CD8 + lymphocytes in the periphery and aberrant CD8+ differentiation into long-lived memory cells suggesting that Lis1 controls homeostasis of T lymphocytes (18).…”

Section: Cytoskeleton Is Involved In the Regulation Of Crucial Cellular Processes Of Ptcl Biologymentioning

confidence: 99%

Cytoskeleton Dynamics in Peripheral T Cell Lymphomas: An Intricate Network Sustaining Lymphomagenesis

et al. 2021

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Defects in cytoskeleton functions support tumorigenesis fostering an aberrant proliferation and promoting inappropriate migratory and invasive features. The link between cytoskeleton and tumor features has been extensively investigated in solid tumors. However, the emerging genetic and molecular landscape of peripheral T cell lymphomas (PTCL) has unveiled several alterations targeting structure and function of the cytoskeleton, highlighting its role in cell shape changes and the aberrant cell division of malignant T cells. In this review, we summarize the most recent evidence about the role of cytoskeleton in PTCLs development and progression. We also discuss how aberrant signaling pathways, like JAK/STAT3, NPM-ALK, RhoGTPase, and Aurora Kinase, can contribute to lymphomagenesis by modifying the structure and the signaling properties of cytoskeleton.

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The Microtubule-Associated Protein Lis1 Regulates T Lymphocyte Homeostasis and Differentiation

Cited by 5 publications

References 41 publications

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

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

Lis1 Regulates Germinal Center B Cell Antigen Acquisition and Affinity Maturation

Cytoskeleton Dynamics in Peripheral T Cell Lymphomas: An Intricate Network Sustaining Lymphomagenesis

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