Age-related changes in magnitude and diversity of cross-reactive CD4+ T-cell responses to the novel pandemic H1N1 influenza hemagglutinin

Accumulating evidence suggests that T-cell responses play a significant role in controlling influenza disease. Although humoral responses to the major antigenic component hemagglutinin (HA) have been studied in considerable detail, our understanding of the cellular responses against this antigen is limited. Here, we systematically characterized the magnitude and diversity of immunity to pandemic H1N1 HA and its relationship to seasonal H1N1 HA responses in a cohort of healthy nonimmunized adults. We observed considerable diversity in the magnitude of crossreactive pandemic CD4+ T-cell responses among the subjects, with a subset of the individuals demonstrating higher magnitude T-cell responses against the pandemic antigen compared with the seasonal antigen. Importantly, the data suggest that age-related changes in CD4+ T-cell responses preferentially segregate to the antigenically drifting globular region of HA, more so than the conserved region involved in membrane fusion. These results have important ramifications for our understanding of influenza immunity in humans and development of vaccine strategies against this important pathogen.