Spatial control of Ca2+ signals in lymphocytes

淋巴细胞活化由多个细胞内信号传导过程组成。这种复杂性使得 淋巴细胞以各种方式调节它们的功能，使得它们的分化和活化被 正确执行。这一复杂系统的损伤可能导致免疫系统的功能障碍， 系统，如自身免疫、过敏和免疫缺陷。 活化T细胞核因子（NF-AT）被认为是最重要的转录因子之一 控制淋巴细胞活化的因子。NF-AT被Ca 2 +/钙调素依赖性激活 磷酸钙神经磷酸酶（CN）。FK 506可抑制NF-AT与CN的相互作用， 环孢菌素A，其广泛用于抑制免疫应答。最近， 几种细胞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，我们鉴定了一种与淋巴特异性Src家族结合的蛋白Repsl， 激酶Lck，并在淋巴细胞中的NF-AT活化中起关键作用。Repsl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Repsl基因的敲除 由于缺乏NF-AT去磷酸化，导致NF-AT活化的消除。NF-at 即使当细胞被绕过细胞的药理学试剂刺激时， 近端信号事件。此外，在T细胞中表达Repsl突变形式的转基因小鼠 显示成熟T细胞产生的IL-2显著减少。数据表明， Repsl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在体外的作用机制及其在体内的生物学意义。

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.