Cytotoxic T lymphocytes (CTLs) are important targets for vaccines against a wide variety of infections that enter the body via mucosal tissues. To induce effective immunity these vaccines must include the most protective epitopes and elicit rapid recall responses at the site of infection. Although live attenuated viruses are sometimes used to induce cellular immunity against recurrent influenza infections, the mechanisms that determine the magnitude of the response to individual viral components are very poorly defined. Heterosubtypic infections in C57BL/6 mice illustrate an additional level of complexity, when the antigen specificity of the response shifts dramatically between primary and secondary challenge. This model provides a unique opportunity to identify the mechanisms that regulate memory CD8(+) T-cell reactivation in vivo and control the specificity of the recall response by pathogen-specific CTL. We show that multiple factors contribute to the changing pattern of immunodominance during secondary infection, including the location of the memory CD8(+) T cells at the time of reinfection and their ability to directly recognize migratory CD103(+) DCs as they arrive in the lung draining LN