The cell and molecular mechanisms underlying CD28 costimulation

 描述（由申请人提供）：CD 28是一种T细胞表面分子，当与固定化TCR配体结合时，可提供第二信号，以诱导幼稚T细胞活化。共刺激是由先天免疫系统的活化在活化的抗原呈递细胞上诱导的CD 28与其配体CD 80（B7.1）和CD 86（B7.2）的相互作用产生的。我们对CD 28如何介导其共刺激信号没有很好的分子理解。模型和实验证据表明，CD 28：1）增加TCR信号传导的幅度;或2）提供独特的信号，与TCR提供的信号在性质上不同。由于阻断共刺激在临床上具有重要意义，因此了解共刺激背后的分子信号通路是很重要的。一个更深入的了解 CD 28信号通路可能使新的治疗方法的发展，将是有用的，在阻断免疫系统。我的实验室最近的研究提供了一些新的见解，并提出了方法和线索，使我们能够识别以前未被识别的CD 28调节信号通路的组成部分，并允许更完整地了解CD 28信号。这些化学生物学、遗传学和蛋白质组学的研究使我们推测，CD 28共刺激的一个重要结果是调节肌动蛋白细胞骨架，这影响TCR下游的信号。我们将通过以下具体的目的来探讨这一点：1）确定共刺激调节肌动蛋白细胞骨架以促进PLCγ1介导的PIP 2水解的机制，2）确定CD 28如何克服Pyk 2和Cbl-b对T细胞信号传导的负调节影响，导致IL-2产生和T细胞增殖;和，3）使用最近获得的磷酸化蛋白质组学数据，我们将确定关键组件的途径下游的CD 28和那些调节肌动蛋白细胞骨架响应CD 28共刺激。

 DESCRIPTION (provided by applicant): CD28 is a T cell surface molecule that can provide a second signal, when combined with immobilized TCR ligands, to induce naïve T activation. Costimulation results from the interaction of CD28 with its ligands CD80 (B7.1) and CD86 (B7.2) induced on activated antigen-presenting cells by activation of the innate immune system. We do not have a good molecular understanding of how CD28 mediates its costimulatory signals. Models and experimental evidence have suggested that CD28 either: 1) augments the magnitude of TCR signaling; or, 2) provides a unique signal, qualitatively distinct from that provided by the TCR. It is important to understand the molecular signaling pathways underlying costimulation since interrupting costimulation has been important clinically. A deeper insight into CD28 signaling pathways may enable the development of new therapeutics that would be useful in blocking the immune system. Very recent studies from my lab provide some new insights and suggest approaches and clues that will enable us identify previously unrecognized components of the CD28-regulated signaling pathways and permit a more complete understanding of CD28 signaling. These chemical-biology, genetic and proteomic studies lead us to hypothesize that an important consequence of CD28 costimulation is the regulation of the actin cytoskeleton and this influences signals downstream of the TCR. We will explore this via the following specific aims: 1) Determine the mechanism by which costimulation modulates the actin cytoskeleton to facilitate PLCγ1 mediated hydrolysis of PIP2 in double positive (CD4+CD8+, DP) thymocytes and in more mature T cells; 2) Determine how CD28 overcomes a negative regulatory influence of Pyk2 and Cbl-b on T cell signaling leading to IL-2 production and T cell proliferation; and, 3) Using recently obtained phosphoproteomic data, we will identify key components of the pathway downstream of CD28 and those that modulate the actin cytoskeleton in response to CD28 costimulation.