Phospholipase a2 contribution to thymocyte maturation and apoptotic thymocyte cell clearence

胸腺是t细胞成熟发生的器官。尽管未成熟t淋巴细胞成熟的不同阶段已经被描述，但其机制仍然不清楚，并在基础免疫学领域产生了吸引力。据估计，胸腺每天产生5000万个未成熟的t细胞，其中只有200万个最终离开胸腺进入血液循环。有趣的是，虽然大多数未成熟的t细胞会发生细胞死亡，但在稳定状态下，只有1-2%的t细胞可以被检测到死亡细胞，这表明死亡t细胞传递的可溶性信号可以促进清道夫细胞（吞噬细胞）的迅速清除。有趣的是，脂质介质的产生被揭示为淋巴细胞成熟的一种机制，尽管脂质释放酶磷脂酶A2 （PLA2）在这一过程中的作用尚不明确。我们发现分泌PLA2组X -一个主要表达于胸腺的分泌PLA2 -参与胸腺细胞凋亡的清除。为了进一步了解PLA2在t淋巴细胞成熟和凋亡中的作用机制，我们将进行以下研究：

The thymus is the organ where the maturation of T-cells occurs. Although the different stages of immature T-lymphocyte maturation have been described, the mechanisms implicated remain obscure and create fascination in the field of basic immunology. It is estimated that 50 million immature T-cells are generated each day in the thymus and that only 2 million ultimately leave the thymus and reach the blood circulation. Intriguingly, while most immature T-cells undergo cell death, only 1-2% can be detected as dying cells in the steady state, suggesting the existence of soluble signals delivered by the dying T-cells to promote prompt clearance by scavenger cells (phagocytes). Interestingly, the generation of lipid mediators was revealed to be a mechanism for lymphocyte maturation, though the role of lipid releasing enzymes phospholipase A2 (PLA2) in this process remained undefined. We found that secreted PLA2 group X - a secreted PLA2 mainly expressed in the thymus - participates to apoptotic thymocyte clearance. To gain further insight into PLA2 mechanism of action in T-lymphocyte maturation and apoptosis we will pursue the following Aims: Aim 1: Define the origin (cell type) of each sPLA2 isoforms expressed in thymic lymphoid and nonlymphoid thymic cells. Aim 2: Investigate the impact of sPLA2 group X expression on thymocyte maturation and apoptosis. Aim 3: Determine the final outcome (downstream biosynthetic products) of sPLA2 group X in the thymus Using both pharmacological and genetic approaches, we will study the contribution of phospholipase A2 to thymocyte maturation and apoptotic thymocyte clearance. While usage of thymic organ cultures and recombinant phospholipase A2 enzymes will permit delineation of phospholipase A2 mechanism in vitro, mouse lacking expression of phospholipase A2 will provide methods of dissection of phospholipase A2 action in vivo.