|Golde, William - Bill|
Submitted to: Clinical and Vaccine Immunology
Publication Type: Peer reviewed journal
Publication Acceptance Date: 12/10/2010
Publication Date: 2/1/2011
Citation: Patch, J.R., Pederesen, L.E., Moraes, M.P., Grubman, M.J., Nielsen, M., Buus, S., Golde, W.T. 2011. Induction of foot-and-mouth disease virus specific cytotoxic T cell killing by vaccination. Clinical and Vaccine Immunology. 18(2):280-288. Interpretive Summary: One of the primary goals of vaccine development for foot-and-mouth disease (FMD) is cross protection for the many serotypes and subtypes of the virus. Many investigators have assumed that targeting the cellular immune response mediated by T cells would be the best chance to achieve cross protection. Anti-viral immunity mediated by T cells involves the induction of cytotoxic T lymphocytes (CTLs) which can lyse virus infected cells in vivo thereby stopping the infection. No one has ever demonstrated antigen specific, CTL killing of virus infected cells in FMD. Here we describe a vaccine strategy that targets the CTL response to FMD virus infection. We clearly demonstrate the killing of infected cells by CTLs from vaccinated animals and show antigen specificity of that response. Further, we confirm the CTL induction by this vaccine using the cutting edge technology of staining with major histocompatibility complex tetramers for the first time in swine. The information is valuable for advancing the technology to control FMD.
Technical Abstract: Foot-and-mouth disease (FMD) continues to be a significant threat to the health and economic value of livestock species. This acute infection is caused by the highly contagious FMD virus which infects cloven-hoofed animals including large and small ruminants and swine. Current vaccine strategies are all directed toward the induction of neutralizing antibody responses. However, the role of cytotoxic T lymphocytes (CTLs) has not received much attention, in part because of the technical difficulties associated with establishing a reliable assay of cell killing for this highly cytopathic virus. Here, we have used recombinant human adenovirus vectors as a means of delivering FMDV antigens in a T cell-directed vaccine. We tested the hypothesis that impaired processing of capsid would enhance cytolytic activity by targeting all proteins for proteosome cleavage and effectively increasing the class I major histocompatibility complex (MHC)/FMDV peptide concentration for stimulation of a CTL response. We compared such a T cell targeting vaccine with the parental vaccine shown to effectively induce a neutralizing antibody response. Our results show induction of FMDV-specific CD8+ CTL killing of MHC matched target cells in an antigen specific manner. Further, we confirm these results by MHC tetramer staining. This work presents the first demonstration of FMDV specific, CTL killing and MHC tetramer staining in response to vaccination against FMDV.