Regulation of the T Cell Cytoskeleton by Costimulation

描述(由申请人提供)：T细胞是适应性免疫系统的中央调节细胞。为了它们的完全激活，TCR对抗原肽/MHC复合体的识别必须通过辅助受体的参与来补充。这种现象被称为共刺激。最主要的辅助受体是CD28和LFA-1。共刺激是医学上相关的干扰，特别是CD28和LFA-1的干扰已被证明在癌症和自身免疫性疾病的治疗中是有用的。在细胞水平上，CD28和LFA-1介导效应细胞因子的分泌，调节T细胞骨架重排。重排对于调节T细胞有效激活的信号复合体的组装至关重要。虽然信号转导在调节效应细胞因子分泌方面已经得到了广泛的研究，但细胞骨架的调节机制尚不清楚。我们建议在这里解决这个问题。 使用最近发展的视频荧光显微镜方法，我们建议在识别与配体结合的TCR或肌动蛋白的同时识别与配体结合的CD28和LFA-1的位置。这将有助于更好地理解共刺激机制。此外，我们建议确定CD28和LFA-1调节T细胞骨架重排的最近端效应蛋白。 对共刺激的更好的理解应该对癌症和自身免疫性疾病的治疗有很大的贡献。

DESCRIPTION (provided by the applicant): T cells are the central regulatory cells of the adaptive immune system. For their complete activation recognition of the antigenic peptide/MHC complex by the TCR has to be complemented by engagement of accessory receptors. This phenomenon is called costimulation. The most prominent accessory receptors are CD28 and LFA-1. Costimulation is medically relevant as interference with costimulation, in particular with CD28 and LFA-1 has proven to be therapeutically useful in the treatment of cancer and autoimmune diseases. At the cellular level CD28 and LFA-1 mediate effector cytokine secretion and regulate T cell cytoskeletal rearrangements. The rearrangements are crucial for the assembly of a signaling complex that mediates efficient T cell activation. While signal transduction in the regulation of effector cytokine secretion has been extensively studied, the mechanism of the cytoskeletal regulation is unknown. We propose to address this question here. Using a recently developed video fluorescence microscopy approach, we propose to identify the location of ligand-engaged CD28 and LFA-1 at the same time as that of the ligand-engaged TCR or that of actin. This will contribute to an improved understanding of the mechanism of costimulation. In addition, we propose to identify the most proximal effector proteins of CD28 and LFA-1 regulating the T cell cytoskeletal rearrangements. An improved understanding of costimulation should significantly contribute to the treatment of cancer and autoimmune diseases.