Spatial control of Ca2+ signals in lymphocytes

淋巴细胞的激活由多种细胞内信号传递过程组成。这种复杂性使得 淋巴细胞以各种方式调节其功能，从而使其分化和激活 妥善执行。这一复杂系统的损伤可能会导致免疫功能失调。 系统，如自身免疫、过敏和免疫缺陷。 核因子活化的T细胞被认为是最重要的转录之一 控制淋巴细胞激活的因素。钙/钙调蛋白依赖性激活核因子-AT 磷酸酶钙调神经磷酸酶(CN)。FK506和FK506可抑制NF-AT与CN的相互作用 环孢菌素A，广泛用于抑制免疫反应。最近， 几种细胞蛋白和病毒蛋白也被确定为CN/NF-AT相互作用的抑制剂。 在初步研究中，我们确定了一种与淋巴特异性Src家族结合的蛋白质Repsl 在淋巴细胞内核因子-AT的活化中起关键作用。Reps1基因高度表达 在胸腺细胞和其他淋巴器官中。鸡B细胞系DT-40中Reps1基因敲除的研究 由于缺乏核因子-AT去磷酸化，导致核因子-AT的激活被取消。核因子-AT 即使细胞被旁路的药物刺激，激活也不会恢复 近端信号事件。此外，在T细胞中表达突变形式的Reps1的转基因小鼠 显示成熟T细胞产生的IL-2显著减少。总而言之，数据表明 Reps1在淋巴细胞活化中起重要作用。在本研究中，我们将详细分析 Repsl的体外作用机制及其体内生物学意义。

Lymphocyte activation consists of multiple intracellular signaling processes. This complexity allows lymphocytes to regulate their function in various ways so that their differentiation and activation are properly carried out. Impairment in this complex system could lead to malfunctioning of the immune system, such as autoimmunity, allergy, and immunodeficiency. Nuclear factor of activated T-cells (NF-AT) is regarded as one of the most important transcription factors that controls lymphocyte activation. NF-AT is activated by Ca2+/calmodulin-dependent phosphatase calcineurin (CN). The interaction between NF-AT and CN is inhibited by FK506 and Cyclosporin A, which are broadly utilized for suppression of the immune responses. Recently, several cellular and viral proteins were also determined as the inhibitors of CN/NF-AT interaction. In the preliminary study, we identify a protein Repslthat binds the lymphoid specific Src family kinase Lck and plays a critical role in NF-AT activation in lymphocytes. Repsl is highly expressed in thymocytes and other lymphoid organs. Gene knockout of Repsl in a chicken B-cell line DT-40 resulted in abolishment of NF-AT activation due to lack of NF-AT dephosphorylation. NF-AT activation was not restored even when cells were stimulated by pharmacological agents that bypass proximal signaling events. Further, transgenic mice expressing a mutant form of Repsl in T cells showed significantly reduced IL-2 production by mature T cells. Together, the data indicates that Repsl plays an essential role in lymphocyte activation. In this study, we will analyze the detailed mechanism of Repsl function in vitro and its biological significance in vivo.