The focus of this proposal is to determine the role of CD8+ T cells in human immunity to an acute viral infection of infancy, respiratory syncytial virus (RSV). For decades, investigators have speculated about the relative importance of cellular versus humoral immunity in protection against disease during reinfection with RSV. Studies to determine the importance of T cells in immunity to RSV are of great interest in terms of basic mechanisms of immunity because of the unusual nature of this mucosally acquired virus and its ability to readily reinfect humans throughout life even though there is a single serotype. Understanding the role of T cells in immunity to RSV also would give us insight into the distinct qualities of the neonatal immune response, which differs significantly both in quality and magnitude from that of older children and adults. The unique dynamics of immunity to RSV in the presence of passive maternal antibodies have been a particular focus of the Pl's work. We also need a much better understanding of the mechanisms of immunity to this virus in order to better design and test new vaccine strategies and candidates. Major efforts are being expended by pharmaceutical firms to develop vaccine candidates for RSV. It is likely that live attenuated and subunit RSV vaccines will differ greatly in the magnitude and specificity of T cell immunity that they induce, but currently we have no way of knowing how to effectively measure T cell immunity or whether it matters. A lot of rodent RSV CTL data has been generated, including numerous publications by the PI on this topic, but we now need sensitive methods for studying RSV-specific T cells in humans. This application shows that the development and application of such methods is now feasible. The hypothesis that we will test is that RSV-specific CD8+ T cells are the principal mechanism of resolution of infection and protection against reinfection during the first months of life, when humoral RSV-specific immunity is profoundly suppressed by passive maternal antibodies.
|Rock, Michael T; McKinney, Brett A; Yoder, Sandra M et al. (2011) Identification of potential human respiratory syncytial virus and metapneumovirus T cell epitopes using computational prediction and MHC binding assays. J Immunol Methods 374:13-7|
|Mok, Hoyin; Lee, Sujin; Wright, David W et al. (2008) Enhancement of the CD8+ T cell response to a subdominant epitope of respiratory syncytial virus by deletion of an immunodominant epitope. Vaccine 26:4775-82|
|Lee, Sujin; Miller, Scott A; Wright, David W et al. (2007) Tissue-specific regulation of CD8+ T-lymphocyte immunodominance in respiratory syncytial virus infection. J Virol 81:2349-58|