Influenza Virus-specific CD8+ T Cells

Influenza viruses are among the leading causes of acute respiratory tract infections worldwide. Natural influenza virus infections elicit both humoral and cellular immune responses. Although, neutralizing antibodies directed to the hemagglutinin (HA) globular head domain prevent reinfection with the same influenza virus they exert limited/no cross-reactivity with antigenically drifted variants or influenza viruses of different strains, it is therefore of interest to identify other correlates of protection. Cellular immunity, especially influenza virus-specific CD8+ cytotoxic T lymphocytes (CTLs), contribute to rapid clearance of influenza virus infections and thereby reduce viral shedding. Influenza virus-specific CTLs, elicited after seasonal influenza virus infections, are mainly directed to conserved internal proteins. In this dissertation we were able to demonstrate the cross-reactivity of seasonal influenza virus-specific CTLs with the novel and potentially pandemic A/H7N9 virus and between different lineages of influenza B viruses. Furthermore, using an unique PBMC donor cohort we were able to assess the longevity of these cells in healthy individuals. In addition, we were able to demonstrate that human influenza A viruses can impair the recognition of the HLA-A0201 restricted and highly conserved M158-66 epitope by specific CTLs by variations in the extra-epitopic amino acids. This CTL evasion strategy may have implications for the viral replication kinetics in HLA-A0201 individuals and thus the spread of influenza A viruses in the human population. Finally, we describe a novel adjuvant, G3/DT, that improves the immunogenicity of a standard inactivated seasonal influenza vaccine in terms of enhancing the antibody response and inducing a protective CTL response.