T cells rely on cell proliferation and migration both during their development inside the thymus and in the periphery to perform immunoprotective functions. Mitochondrial dynamics and in particular Drp1dependent mitochondrial fragmentation deeply affect both these processes in several other different cellular contexts. Moreover, mature polarized T cell relies on mitochondrial accumulation at the back-located uropod to correctly migrate. Therefore, in this work, we decided to investigate whether Drp1 could have a role in development and different physiological functions of the adaptive immune system. Here we show that conditional removal of Drp1 in T lymphocyte lineage, starting from the stage of developing thymocyte, results in a reduction of proliferation capability of both developing and activated T cells due to a longer mitosis length. Furthermore, impairment of T lymphocytes to accumulate mitochondria at the uropode in absence of Drp1 causes a reduction in migration of thymocytes inside thymus, with a consequent increase in cell death sensitivity in cortical areas and a reduced accumulation of medullary thymocytes. Similarly, also mature T cells show an impairment in transmigration across endothelial barriers. This gives rise to an in vivo defective recirculation of T cells inside secondary lymphoid organs and inflamed sites. Together these findings suggest that Drp1 conditional KO mice could develop an immunodeficient phenotype when the immune system is challenged. Indeed, injection of subcutaneous tumours into Drp1 conditional KO mice results in a faster tumour growth due to a reduced capability of T cells to infiltrate the tumoural mass.

(2015). The Role of the mitochondria profission protein DRP1 in T cell development and function.

The Role of the mitochondria profission protein DRP1 in T cell development and function

SIMULA, LUCA
2015-01-01

Abstract

T cells rely on cell proliferation and migration both during their development inside the thymus and in the periphery to perform immunoprotective functions. Mitochondrial dynamics and in particular Drp1dependent mitochondrial fragmentation deeply affect both these processes in several other different cellular contexts. Moreover, mature polarized T cell relies on mitochondrial accumulation at the back-located uropod to correctly migrate. Therefore, in this work, we decided to investigate whether Drp1 could have a role in development and different physiological functions of the adaptive immune system. Here we show that conditional removal of Drp1 in T lymphocyte lineage, starting from the stage of developing thymocyte, results in a reduction of proliferation capability of both developing and activated T cells due to a longer mitosis length. Furthermore, impairment of T lymphocytes to accumulate mitochondria at the uropode in absence of Drp1 causes a reduction in migration of thymocytes inside thymus, with a consequent increase in cell death sensitivity in cortical areas and a reduced accumulation of medullary thymocytes. Similarly, also mature T cells show an impairment in transmigration across endothelial barriers. This gives rise to an in vivo defective recirculation of T cells inside secondary lymphoid organs and inflamed sites. Together these findings suggest that Drp1 conditional KO mice could develop an immunodeficient phenotype when the immune system is challenged. Indeed, injection of subcutaneous tumours into Drp1 conditional KO mice results in a faster tumour growth due to a reduced capability of T cells to infiltrate the tumoural mass.
2015
2015/2016
Biologia cellulare e molecolare
29.
Settore BIO/11 - BIOLOGIA MOLECOLARE
English
Tesi di dottorato
(2015). The Role of the mitochondria profission protein DRP1 in T cell development and function.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/201669
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