Control of CD8+ T cell activation and differentiation by the signaling adaptor BCAP

项目摘要 CD 8 + T细胞整合来自T细胞受体、共刺激分子和细胞因子的信号， 它们的克隆扩增和分化成终末效应细胞或长寿命细胞的特化群体， 记忆细胞虽然效应和记忆CD 8 + T细胞的产生是清除CD 8 + T细胞所必需的， 细胞内感染，并形成针对广泛病原体的疫苗接种策略的基础， 在抗癌免疫治疗中，CD 8 + T细胞也可引起自身免疫组织损伤，并且是免疫治疗的屏障。 有效的组织移植。因此，了解CD 8 + T细胞扩增的分子控制， 分化和功能的研究将在操纵CD 8 + T细胞应答中具有广泛的应用。 疫苗接种和感染性疾病、自身免疫、移植和肿瘤免疫治疗的背景。 然而，尽管进行了广泛的研究，但我们对指导分化、功能 并且不同群体的效应和记忆CD 8 + T细胞的稳态仍然不完全。我们有 提出了一个新的观察，即信号转导衔接子BCAP在CD 8 + T细胞活化后迅速上调， 细胞此外，我们发现BCAP的缺失损害了CD 8 + T细胞的正常克隆扩增，并改变了 效应/记忆细胞分化。因此，我们已经确定BCAP是一个关键的， 未表征的信号中枢，有助于控制CD 8 + T细胞活化的结果。因此， 了解BCAP的功能和识别其相关的信号通路将有助于确定分子 为CD 8 + T细胞的治疗性操作提供了新的靶点 应答在本提案中，我们将在这些令人兴奋的初步研究的基础上， BCAP依赖性信号传导如何影响效应器和记忆的增殖、分化和功能 CD 8 + T细胞，并确定BCAP调节的关键分子通路，帮助控制这些细胞中的每一个。 流程.

Project Summary CD8+ T cells integrate signals from the T cell receptor, co-stimulatory molecules, and cytokines that control their clonal expansion and differentiation into specialized populations of terminal effector cells or long-lived memory cells. Although the generation of effector and memory CD8+ T cells is required for clearance of intracellular infections and forms the basis for vaccination strategies against a wide-range of pathogens and anti-cancer immunotherapy, CD8+ T cells can also cause autoimmune tissue damage, and are a barrier to effective tissue transplantation. Thus, understanding the molecular control of CD8+ T cell expansion, differentiation and function will have wide-ranging applications in manipulating CD8+ T cell responses in the contexts of vaccination and infectious disease, autoimmunity, transplantation and tumor immunotherapy. However, despite extensive study our knowledge of the key molecules that direct the differentiation, function and homeostasis of different populations of effector and memory CD8+ T cells remains incomplete. We have made the novel observation that the signaling adaptor BCAP is rapidly upregulated upon activation of CD8+ T cells. Moreover, we show that loss of BCAP impairs normal clonal expansion of CD8+ T cells and alters effector/memory cell differentiation. Thus, we have identified BCAP as a critical and previously uncharacterized signaling hub that helps control the outcome of CD8+ T cell activation. Thus, better understanding BCAP function and identifying its associated signaling pathways will help define the molecular basis for CD8+ T cell function, and provide new targets for therapeutically manipulating of CD8+ T cell responses. In this proposal, we will build on these exciting preliminary studies to comprehensively determine how BCAP-dependent signaling impacts the proliferation, differentiation and function of effector and memory CD8+ T cells, and to define the key molecular pathways regulated by BCAP that help control each of these processes.