The cell and molecular mechanisms underlying CD28 costimulation

CD 28是T细胞表面分子，当与固定的TCR结合时，其可以提供第二信号 配体，以诱导幼稚T活化。CD 28与其配体CD 80相互作用产生共刺激 通过激活先天性免疫细胞在活化的抗原呈递细胞上诱导的CD 86（B7.1）和CD 86（B7.2） 系统我们对CD 28如何介导其共刺激信号还没有很好的分子理解。 模型和实验证据表明，CD 28：1）增加TCR的大小 信号传导;或2）提供独特的信号，其在性质上不同于TCR提供的信号。重要的是要 了解共刺激的分子信号通路，因为中断共刺激 在临床上很重要。深入了解CD 28信号通路可能有助于开发新的 这将有助于阻断免疫系统的治疗。我实验室最近的研究提供了 一些新见解和建议的方法和线索，将使我们能够确定以前没有认识到的 CD 28调节信号通路的组成部分，并允许更完整地了解CD 28 发信号。这些化学生物学、遗传学和蛋白质组学的研究使我们假设， CD 28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以促进PLCγ1介导的 在双阳性（CD 4 + CD 8+，DP）胸腺细胞和更成熟的T细胞中的PIP 2; 2）确定CD 28 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， T细胞增殖; 3）使用最近获得的磷酸化蛋白质组学数据，我们将确定T细胞增殖的关键组分。 CD 28下游通路和那些响应于CD 28调节肌动蛋白细胞骨架的通路 共刺激

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.