Flaviviruses - Yin Yang of Heterologous T Cell Immunity

黄病毒科包括出血热病毒(如登革热病毒、黄热病病毒)和 脑炎病毒(例如西尼罗河病毒、日本脑炎病毒)。这样做的长期目标是 项目是确定黄病毒特异性的CD4+和CD8+T细胞反应的影响 黄病毒感染对免疫反应的影响与后续感染黄病毒相关。 在具体目标1中，我们将表征效应器反应、TCR亲和力和对同源和 初级黄病毒免疫个体中的异源病毒CD4+和CD8+T细胞表位。 在特定目标2中，我们将产生对不同表位的初级黄病毒CD4+和CD8+T细胞反应 来自黄病毒-NATve个体和人类人类白细胞抗原转基因小鼠。我们将交叉反应描述为 并将我们在体外的发现与体内产生的结果进行比较。 在特定的目标3中，我们将确定我们的体外研究结果的生物学相关性。我们将定义变量 顺序感染黄病毒的人的特异性反应。使用人类人类白细胞抗原转基因小鼠，我们将 用西尼罗河病毒亚临床多肽免疫建立原发和继发反应模型 感染。最后，我们将与项目2合作，确定不同T细胞刺激的效果 人T细胞在原代人内皮细胞上的表达。 这些研究将有助于阐明交叉保护的机制，并可能对疾病有深入的了解。 发病机制。

The family Flaviviridae includes hemorrhagic fever viruses (e.g. dengue viruses, yellow fever virus) and encephalitis viruses (e.g. West Nile virus, Japanese encephalitis viruses). The long-term objective of this project is to determine the effect of flavivirus-specific CD4+ and CD8+ T cell responses induced by primary flavivirus infection on the immune response to subsequent infection with related flaviviruses. In Specific Aim 1, we will characterize effector responses, TCR avidity and signaling to homologous and heterologous virus CD4+ and CD8+ T cell epitopes in primary flavivirus-immune individuals. In Specific Aim 2, we will generate primary flavivirus CD4+ and CD8+ T cell responses to variant epitopes from flavivirus-naTve individuals and in human HLA transgenic mice. We will characterize cross-reactivity as in Aim 1 and will compare our findings in vitro to those generated in vivo. In Specific Aim 3, we will determine the biologic relevance of our in vitro findings. We will define variant specific responses in humans with sequential flavivirus infections. Using human HLA transgenic mice, we will model primary and secondary responses using peptide immunization followed by subclinical West Nile virus infection. Lastly, in collaboration with Project 2, we will determine the effect of variant T cell stimulation of human T cells on primary human endothelial cells. These studies will help to elucidate mechanisms of cross-protection and may give insights into disease pathogenesis.