Multiple Pathways of CD28 Costimulation

CD28 共刺激的多种途径

• 批准号: 7068576
• 负责人: JIM F Miller
• 金额: $ 34.28万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7068576
• 关键词: CD28 molecule; T lymphocyte; biological signal transduction; genetic transcription; genetically modified animals; interleukin 2; laboratory mouse; leukocyte activation /transformation; messenger RNA; phosphatidylinositol 3 kinase; protein kinase; protein kinase C

DESCRIPTION (provided by applicant): It is well established that costimulation through CD28 can have a dramatic effect on T cell activation, survival, tolerance, and differentiation. However, in spite of considerable interest and effort, it has been unclear whether these different functions of CD28 are all mediated simply through amplification of TCR signaling or through the induction of one or more distinct signaling pathways. We have recently found that CD28 can transduce two independent signaling pathways that result in the upregulation of IL-2 secretion. One pathway is dependent in the ability of CD28 to activate phosphatidylinositol 3-kinase (PI3K) and results in the specific recruitment of PKCtheta to the cSMAC region of the immunological synapse, nuclear translocation of NF-kappaB, and upregulation of IL-2 transcription. This pathway may be mediated through proximal signal integration between TCR and CD28 signaling within the context of specific localization of proteins within the immunological synapse. The second pathway functions in the absence of CD28-mediated activation of PI3K and does not induce recruitment of PKCtheta to the immunological synapse or upregulation of IL-2 transcription. Nevertheless, costimulation through CD28 that cannot activate PI3K still induces normal levels of IL-2 secretion primarily through stabilization of IL-2 mRNA. This pathway also appears to function when CD28 costimulation is provided in trans and so may be mediated by signal integration downstream from the plasma membrane. The overall goal of this proposal is to define the cell biological, biochemical, and molecular steps that mediate these two independent pathways of CD28 costimulation. We will accomplish these goals through two specific aims: 1. Determine how targeting of CD28 and associated signaling molecules to the cSMAC impacts on CD28 costimulation of IL-2 transcription. 2. Identify the components of the PI3-kinase-independent CD28 signaling pathway that lead to IL-2 mRNA stabilization.

描述（由申请人提供）：已经确定，通过CD 28的共刺激可以对T细胞活化、存活、耐受和分化产生显著影响。然而，尽管有相当大的兴趣和努力，但尚不清楚CD 28的这些不同功能是否都是简单地通过TCR信号传导的扩增或通过诱导一种或多种不同的信号传导途径介导的。我们最近发现，CD 28可以通过两条独立的信号通路上调IL-2的分泌。一种途径依赖于CD 28激活磷脂酰肌醇3-激酶（PI 3 K）的能力，并导致PKC θ特异性募集至免疫突触的cSMAC区域、NF-κ B核转位和IL-2转录上调。该途径可以通过在免疫突触内蛋白质的特异性定位的背景下TCR和CD 28信号传导之间的近端信号整合来介导。第二途径在不存在CD 28介导的PI 3 K活化的情况下起作用，并且不诱导PKC θ向免疫突触的募集或IL-2转录的上调。然而，通过不能激活PI 3 K的CD 28的共刺激仍然主要通过稳定IL-2 mRNA诱导正常水平的IL-2分泌。当以反式提供CD 28共刺激时，该途径似乎也起作用，因此可能由质膜下游的信号整合介导。该提案的总体目标是确定介导这两个独立的CD 28共刺激途径的细胞生物学、生物化学和分子步骤。 我们将通过两个具体目标实现这些目标： 1.确定CD 28和相关信号分子靶向cSMAC如何影响IL-2转录的CD 28共刺激。 2.鉴定导致IL-2 mRNA稳定的PI 3激酶非依赖性CD 28信号通路的组分。