NK cell regulation of adaptive virus immunity

NK细胞调节适应性病毒免疫

• 批准号: 7746099
• 负责人: Michael G Brown
• 金额: $ 28.08万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-18 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7746099
• 关键词: Adoptive Transfer; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antigen Presentation; Antiviral Agents; Binding; Biological Assay; CD8B1 gene; Cell Communication; Cell Differentiation process; Cell Surface Receptors; Cell physiology; Cells; Complex; Congenic Strain; Cytomegalovirus Infections; Data; Dendritic Cells; Epitopes; Equilibrium; Flow Cytometry; Frequencies; Genes; Genetic; Genetic Models; ITGAX gene; Immune; Immune response; Immunity; Infection; Inflammatory; Injury; Interferon Type I; Interferons; Interleukin-10; Kinetics; Knock-in Mouse; Laboratories; Link; MHC Class I Genes; Mediating; Modeling; Monitor; Mouse Strains; Murid herpesvirus 1; Mus; Mutation; NK Cell Activation; Natural Immunity; Natural Killer Cells; Nature; Production; Proteins; Publishing; Recombinants; Regulation; Reporter; Research Project Grants; Research Proposals; Resistance; Role; Shapes; Site; Spleen; Surface; Surveys; System; T-Lymphocyte; Testing; Time; Tissues; Transgenic Organisms; Viral; Virus; Virus Activation; Virus Diseases; Virus Replication; base; cell type; cytokine; cytotoxicity; fight against; killings; novel; receptor; response; viral resistance

NK cells are needed in the body to kill virus infected cells. NK-mediated virus immunity has been linked with innate cytokines (e.g. type I interferons), sustained dendritic cells and accelerated acquisition of virus specific effector T cells in infected animals. However, little is known about how efficient NK-mediated virus immunity can regulate and shape maturation and/or activation profiles of other immune cells. This proposal is based on a new genetic model for NK-mediated virus immunity under MHC control in two recombinant congenic strains of mice referred to as R2 and R7. R2 and R7 only differ by ~300-kb in the MHC class I D subregion, but NK-mediated virus immunity is remarkable in R7 mice. The broad long-term objective for this research project seeks to examine how efficient NK-mediated virus immunity can impart dramatic control over immune cells, in addition to their critical function in innate immunity, through controlled genetic comparisons. A guiding hypothesis is that NK-mediated virus control differences in R2 and R7 will be linked with induction of adaptive immunity through regulation of a fine balance of cytokines before virus levels differ significantly. Three specific aims are proposed: Aim 1. To determine the effect of MHC regulated NK cell function on the induction and kinetics of the CD8+ T cell response to MCMV infection. CD8+ CTLs from R2 and R7 will be assessed in flow cytometric and cytotoxicity assays to ascertain the induction time course, response magnitude, activation state and effector activity after infection. Adoptive transfers with CD8+ TCR transgenic T-cells will further define the induction and the effector activity CDS T cells responding in the spleens of resistant and susceptible mice. Aim 2. To analyze the effect of NK cell-DC interactions on splenic NK cell function. Activation states for splenic NK cells and the frequency and subset distribution of CDllc+ DCs after infection of R2 and R7 will be analyzed using flow cytometry. Splenic cytokine production, especially type 1 interferon and IL-10, will be evaluated via multiplex cytokine assays. Aim 3. To examine a potential causal role for IL-10 underlying MHC regulated differences in NK cell-mediated virus immunity. A potential regulatory role for IL-10 on the induction of adaptive immunity will be evaluated in IL10GFP knock-in reporter mice and IL-10 deficient mice

人体需要NK细胞来杀死病毒感染的细胞。nk介导的病毒免疫与