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Introduction
Influenza viruses are a major cause of respiratory tract infections in humans. Annual epidemic outbreaks are typically caused by influenza A (H1N1 or H3N2 subtypes) or B viruses. Complications leading to morbidity and mortality following infection are predominantly observed in high-risk groups, such as the elderly and immunocompromised. Therefore, annual vaccination of these high-risk groups is recommended.
Currently used trivalent inactivated influenza vaccines (TIV) contain hemagglutinin (HA) of A/H1N1, A/H3N2 and influenza B vaccine strains that antigenically match the epidemic strains that are most likely to circulate in the coming influenza season. Recently, quadrivalent vaccines have become available that contain an additional, antigenically different influenza B virus component [1] . These vaccines aim at the induction of antibody responses against HA and to a lesser extent neuraminidase (NA) [2] and their use reduces morbidity and mortality in selected patient populations [3] . However, as a result of selective pressure exerted by virus-specific antibodies induced by previous vaccinations and/or infections, seasonal influenza viruses accumulate mutations in the antigenic sites of HA and NA [4-6] . Therefore, vaccine-induced antibodies do not provide efficient protection against infection with antigenically mismatching virus strains. In general, TIV inefficiently induce virus-specific CD8+ T cell responses [7,8] that also substantially contribute to protective immunity by accelerating viral clearance. Live-attenuated influenza vaccines (LAIV) are also available in some countries and are especially used to vaccinate children [9] . LAIV are capable of inducing both humoral and cellular immune responses, and induce both cytotoxic and helper T cells [10] .
In this review, we describe the induction of T cell responses by influenza virus infections. Subsequently, we discuss the role of both CD4+ and CD8+ T cells in the clearance of influenza virus infections and their contribution to heterosubtypic immunity. Furthermore, we discuss vector-based vaccination strategies that focus on efficient induction of a cross-reactive influenza virus-specific T cell response and afford heterosubtypic immunity.
Immune response to influenza virus
Influenza virus-specific serum antibodies are detected 7-12 days post primary infection. Neutralizing antibodies mainly target the HA and NA proteins and correspond well with protection from infection with homologous strains [11] . Infection with (seasonal) influenza virus also induces T cell responses [12-16] . Since influenza viruses infect epithelial cells of...