The cell and molecular mechanisms underlying CD28 costimulation

 描述(申请人提供)：CD28是一种T细胞表面分子，当与固定的TCR配体结合时，可以提供第二个信号来诱导幼稚的T细胞激活。共刺激是CD28与其配体CD80(B7.1)和CD86(B7.2)相互作用的结果，通过激活天然免疫系统诱导活化的抗原提呈细胞。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信号的大小；或者，2)提供与TCR信号性质不同的独特信号。由于干扰共刺激在临床上具有重要意义，因此了解协同刺激背后的分子信号通路是很重要的。更深入地了解 CD28信号通路可能会使新疗法的开发成为可能，这种疗法将有助于阻断免疫系统。我的实验室最近的研究提供了一些新的见解，并提出了一些方法和线索，这些方法和线索将使我们能够确定CD28调节的信号通路中以前未识别的成分，并允许更完整地了解CD28信号。这些化学生物学、遗传学和蛋白质组学的研究使我们假设CD28共刺激的一个重要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讨这一点：1)确定共刺激调节肌动蛋白细胞骨架的机制，以促进PLCγ1在双阳性(CD 4+CD 8+，DP)胸腺细胞和更成熟的T细胞中介导PIP2的水解；2)确定CD28如何克服PYK2和Cb1-b对T细胞信号的负面调节影响，从而导致IL-2的产生和T细胞的增殖；以及，3)利用最近获得的磷蛋白质组数据，我们将确定CD28下游通路的关键成分以及那些响应于CD28共刺激而调节肌动蛋白细胞骨架的关键成分。

 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.