: Influenza virus infections are a significant clinical problem and there is particular concern that highly virulent strains may emerge, either through natural mechanism, or through terrorist actions. Despite the impact of influenza viruses on human health, satisfactory vaccines have not been developed. It has been established that cytotoxic CD8+ T cells play a critical role in the control of influenza virus infections. However, the mechanisms controlling the specificity and magnitude of CD8+ T cell responses are poorly understood. This proposal investigates the regulation of T cell responses to two T cell epitopes in C57BL/6 mice (NP[366-374]/Db and PA[224-233]/Db). Whereas equivalent T cell responses are generated to these epitopes during a primary response, NP[366-374]/Db-specific T cells dominate the secondary response. Interestingly, these epitopes are differentially expressed in cell lines infected with influenza virus in vitro. Thus, the PA[224-233]/Db epitope appears to be exclusively expressed in dendritic cells whereas the NP[366- 374]/Db epitope is expressed in all cell lines tested. Based on these observations, we hypothesize that differences in antigen presentation in macrophages and dendritic cells regulate the immunodominance of the T cell response in vivo. This hypothesis will be tested in aim 1 by analyzing the expression of the NP[366-374]/Db and PA[224-233]/Db epitopes in different cell types in vivo. The relationship between epitope expression and the capacity to drive T cell responses will also be investigated. The impact of vaccination on the immunodominance patterns and efficacy of NP[366-374]/Db and PA[224-233]/Db specific T cells will be analyzed in aim 2.
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| Crowe, Sherry R; Turner, Stephen J; Miller, Shannon C et al. (2003) Differential antigen presentation regulates the changing patterns of CD8+ T cell immunodominance in primary and secondary influenza virus infections. J Exp Med 198:399-410 |
