Rôles dans les lymphocytes T de la protéine Lis1, un régulateur de la dynamique des microtubules dépendante de la dynéine

Abstract : The T cell receptor (TCR) is assembled during the early development of T lymphocytes in the thymus after complexe genetic recombinations. The rearrangement of a functional TCR beta-chain (pre-TCR) triggers intracellular signaling pathways that cause the survival, expansion and maturation of thymocytes. The commitment of the TCR to the surface of mature T cells after antigen recognition also leads to proliferation allowing the development of effective immune responses. These cellular events go along with significant reorganization of the microtubule networks and a redistribution of molecular motors, such as dynein, which transport the cellular structures via this network. The molecular mechanisms and physiological consequences of the reorganization are poorly understood in T cells. Lis1 is a dynein regulator involved in neuronal migration and stem cells proliferation during neural development. Its role in lymphoid tissue is still unknown. In this study, we used mouse models specifically Lis1-deficient in T cells to study the molecular, cellular and physiological functions of this protein in T cells. We identifiy that Lis1 plays an essential role in the early development of T cells and in the homeostasis of mature cells. Lis1 deficiency does not affect beta-chain rearrangement or signaling events triggered by pre-TCR or TCR, but leads to the blockage of thymocyte cell division that have undergone beta-selection or mature T cells stimulated. Fine analysis of mitosis indicates that the deficiency of Lis1 strongly slows down the mitotic process, counteracts the cell changes leading to the metaphase and leads to asymmetric distribution of the genetic material in the daughter cells. Microtubule networks analysis shows that the absence of Lis1 induces centrosomes amplification and increase of multipolar cells during mitosis. Finally, we show that Lis1 promotes the dynein-dynactin interaction, indicating that Lis1 plays an important role in T cells to bind dynein to the cell structures it carries. In conclusion, we here described that Lis1 is important for the distribution of genetic material during double negative thymocyte and peripheral lymphocyte proliferation.
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Jérémy Argenty. Rôles dans les lymphocytes T de la protéine Lis1, un régulateur de la dynamique des microtubules dépendante de la dynéine. Immunologie. Université Paul Sabatier - Toulouse III, 2018. Français. ⟨NNT : 2018TOU30123⟩. ⟨tel-02277145⟩

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