CD8plus cytotoxic T lymphocytes (CTL) play a central role in the immune response to infection by respiratory viruses by specifically eliminating vitally infected cells. The CTL response tends to focus on a limited number of dominant antigenic epitopes, while other epitopes (referred to as subdominant epitopes) are apparently ignored. Nonetheless, it is becoming increasingly clear that subdominant epitopes have the potential to drive potent CTL responses under the appropriate circumstances. The current proposal investigates the establishment and recall requirements of memory to both subdominant and dominant T cell epitopes. Studies will focus on Sendai virus infection of mice, a model for human type 1 parainfluenza virus infections responsible for severe respiratory tract disease in children. Preliminary data show that there is strong priming of memory CTL specific for a subdominant epitope, but that effector cells of this specificity are not represented in the acute response to Sendai virus infection. These data suggest that there are differential requirements for generating effector and memory T cells.
In Aim 1, the requirements for establishing and recalling memory to subdominant epitopes will be investigated. In addition, the long- term stability of this memory in aged mice will be analyzed. These studies will be extended to other subdominant epitopes in Aim 2 with a view to identifying those that are able to induce memory CTL and defining the relationship between the immunodominance hierarchy and the establishment of memory.
In Aim 3 the effects of vaccinating mice to subdominant epitopes will be investigated in terms of the subsequent CTL response and protection. Finally, in Aim 4, primary and memory CTL responses to Sendai infection will be compared to determine whether fine-specificity and T cell receptor usage change in the course of an immune response. Taken together, these studies will extend our understanding of immunodominance and the establishment of T cell memory during viral infections in general and will be invaluable for the development of vaccines designed to emphasize cell-mediated immunity.
| Cauley, Linda S; Hogan, Robert J; Woodland, David L (2002) Memory T-cells in non-lymphoid tissues. Curr Opin Investig Drugs 3:33-6 |
| Zhong, W; Roberts, A D; Woodland, D L (2001) Antibody-independent antiviral function of memory CD4+ T cells in vivo requires regulatory signals from CD8+ effector T cells. J Immunol 167:1379-86 |
| Hogan, R J; Zhong, W; Usherwood, E J et al. (2001) Protection from respiratory virus infections can be mediated by antigen-specific CD4(+) T cells that persist in the lungs. J Exp Med 193:981-6 |
| Woodland, D L; Hogan, R J; Zhong, W (2001) Cellular immunity and memory to respiratory virus infections. Immunol Res 24:53-67 |
| Hogan, R J; Usherwood, E J; Zhong, W et al. (2001) Activated antigen-specific CD8+ T cells persist in the lungs following recovery from respiratory virus infections. J Immunol 166:1813-22 |
