Flaviviruses - Yin Yang of Heterologous T Cell Immunity

黄病毒科包括出血热病毒（例如登革热病毒、黄热病病毒）和 脑炎病毒（例如西尼罗河病毒、日本脑炎病毒）。长期目标是 项目是确定黄病毒特异性CD4+和CD8+ T细胞应答的影响， 黄病毒感染对随后感染相关黄病毒的免疫应答的影响。 在特异性目标1中，我们将表征效应子应答、TCR亲合力和对同源和 异源病毒CD4+和CD8+ T细胞表位在原代黄病毒免疫个体中的表达。 在特异性目标2中，我们将产生对变体表位的初级黄病毒CD4+和CD8+ T细胞应答 来自黄病毒天然个体和人HLA转基因小鼠。我们将交叉反应性描述为 在目标1中，并将我们在体外的发现与体内产生的结果进行比较。 在具体目标3中，我们将确定我们体外发现的生物学相关性。我们将定义变量 在连续黄病毒感染的人类中的特异性反应。使用人类HLA转基因小鼠，我们将 使用肽免疫随后亚临床西尼罗河病毒的模型初级和次级应答 感染最后，与项目2合作，我们将确定变体T细胞刺激对 人T细胞对原代人内皮细胞的作用。 这些研究将有助于阐明交叉保护的机制，并可能使人们深入了解疾病 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.