The cell and molecular mechanisms underlying CD28 costimulation

CD28是一种T细胞表面分子，当与固定的TCR结合时，可以提供第二信号 配体，以诱导幼稚T细胞的激活。CD28与其配体CD80相互作用产生的共刺激效应 (B7.1)和CD86(B7.2)通过激活天然免疫诱导活化的抗原提呈细胞 系统。对于CD28如何介导其共刺激信号，我们在分子水平上还没有很好的了解。 模型和实验证据表明，CD28可以：1)增加TCR的幅度 信令；或者，2)提供与TCR提供的信号在性质上不同的唯一信号。重要的是要 了解自中断共刺激以来潜在的共刺激的分子信号通路 在临床上很重要。对CD28信号通路的深入了解可能有助于开发新的 对阻断免疫系统有用的治疗方法。我实验室的最新研究提供了 一些新的见解和建议的方法和线索，将使我们能够识别以前没有认识到的 CD28调节的信号通路的组成部分，使我们对CD28有更全面的了解 发信号。这些化学生物学、遗传学和蛋白质组学研究引导我们假设，一个重要的 CD28共刺激的结果是肌动蛋白细胞骨架的调节，这影响了 TCR下游的信号。我们将通过以下具体目标来探索这一点：1)确定 共刺激调节肌动蛋白细胞骨架促进PLCγ-1介导的水解酶的机制 PIP2在双阳性(CD4、CD8、DP)胸腺细胞和更成熟的T细胞中的表达；2)决定CD28如何 克服了Pyk2和Cbl-b对T细胞信号转导导致IL-2产生的负面调节影响，并 T细胞增殖；以及，3)使用最近获得的磷酸蛋白质组数据，我们将确定 CD28下游通路及其对CD28的细胞骨架调控作用 共刺激效应。

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.