Processing and Presentation of Ectromelia Virus to CD4+ T Lymphocytes

项目3由两个概念驱动。首先，CD4 + T淋巴细胞（TCD4+），它识别病毒衍生的 MHC II类分子中的肽对于宿主驱动和增强适应性至关重要 反应和建立免疫记忆。第二，病原体与它们之间的相互作用 自然宿主是非常复杂的实验系统，在这些系统中，病毒和宿主都没有 共同进化的风险错过了对这些关系的关键见解。尽管如此，很少有研究表明 TCD4+对自然感染的反应。鼠痘病毒（ECTV）提供了这种 在一个高度相关的模式，具有广泛的资格的机会。虽然关系密切， 许多研究牛痘病毒（VACV）不是小鼠病原体，所有三个实验室的初步结果表明， 发现了ECTV和VACV反应之间的许多根本差异。因此，我们预计， 在抗性和易感小鼠中系统检查TCD4+对ECTV与VACV的反应， 揭示具有广泛相关性的见解。这个高度综合的项目有四个独立的，但主题 连接的目标。目的1：确定TCD4+应答的肽靶点，确定TCD4+应答的加工途径 负责它们的产生，并询问肽身份是否决定了TCD4+表型。这项工作将 在目标2中通过成像研究来补充，成像研究将在体内鉴定相关的抗原呈递细胞， 确定不同类型的抗原如何在体内呈递，并检查TCD4+的动态 感染后激活。在第三个目标中，我们将评估肽在保护性免疫中的作用。 由非经典但普遍的胞质加工途径产生。最后，已公布和初步 数据表明VACV干扰II类限制性肽呈递。在目标4中，我们将评估 ECTV致力于这一努力的程度。除了提供有关 TCD4+在自然感染中的作用，项目3的结果与高度互补的 项目1和2形成了一个全面的图片ECTV/鼠标动态。这张照片不仅会 为该计划提供了未来的方向，但也深入了解了许多其他病毒/宿主关系。

Project 3 is motivated by two concepts. First, CD4+ T lymphocytes (TCD4+), which recognize virus-derived peptides in the context of MHC class II molecules, are vital to the host in driving and potentiating adaptive responses and establishing immunological memory. Second, the interplay between pathogens and their natural hosts is exquisitely complex and experimental systems in which the virus and host have not coevolved risk missing crucial insights into these relationships. Despite this, there have been few studies of TCD4+ responses to a natural infection. Ectromelia virus, (ECTV) the mouse poxvirus, provides this opportunity in a highly relevant model featuring a broad range of susceptibilities. Though closely related, the much studied vaccinia virus (VACV) is not a mouse pathogen and preliminary results from all three labs have identified many fundamental differences between responses to ECTV and VACV. Thus, we expect that a systematic examination of the TCD4+ response to ECTV vs. VACV in resistant and susceptible mice will reveal insights with broad relevance. This highly integrated project has four independent but thematically connected aims. Aim 1 will define the peptide targets of TCD4+ responses, identify the processing pathways responsible for their generation, and ask whether peptide identity dictates TCD4+ phenotype. This work will be complemented in Aim 2 by imaging studies which will identify the relevant antigen presenting cells in vivo, determine how different types of antigen are presented in vivo, and examine the dynamics of TCD4+ activation following infection. In the third aim we will assess the role in protective immunity of peptides generated by a nonclassical but prevalent cytosolic processing pathway. Finally, published and preliminary data indicate that VACV interferes with class ll-restricted peptide presentation. In aim 4, we will assess the degree to which ECTV is committed to this endeavor. In addition to providing valuable information about the roles of TCD4+ in a natural infection, results from Project 3 integrate with those of the highly complementary Projects 1 and 2 to form a comprehensive picture of the ECTV/mouse dynamic. This picture will not only provide future directions for the program, but also insights into many other virus/host relationships.