Regulation of the T Cell Cytoskeleton by Costimulation

描述（由申请方提供）：T细胞是适应性免疫系统的中心调节细胞。为了它们的完全活化，TCR对抗原肽/MHC复合物的识别必须通过辅助受体的接合来补充。这种现象被称为共刺激。最主要的辅助受体是CD 28和LFA-1。共刺激在医学上是相关的，因为干扰共刺激，特别是干扰CD 28和LFA-1，已被证明在治疗癌症和自身免疫性疾病中是治疗上有用的。在细胞水平，CD 28和LFA-1介导效应细胞因子分泌并调节T细胞细胞骨架重排。重排对于介导有效T细胞活化的信号复合物的组装至关重要。虽然信号转导调节效应细胞因子分泌已被广泛研究，细胞骨架调节的机制是未知的。我们建议在此解决这个问题。 使用最近开发的视频荧光显微镜的方法，我们建议确定的配体接合的CD 28和LFA-1的位置，在同一时间的配体接合的TCR或肌动蛋白。这将有助于更好地了解共刺激的机制。 此外，我们建议确定最近的效应蛋白的CD 28和LFA-1调节T细胞骨架重排。 对共刺激的进一步理解将对癌症和自身免疫性疾病的治疗做出重大贡献。

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.