The influence of diet-induced obesity on the generation, function and maintenance of influenza-specific memory CD8+ T cells

In both humans and animal models, obesity leads to a dysregulated immune response; however, the effect of obesity on response to viral infection is largely unknown. Yearly outbreaks of influenza virus are a major cause of morbidity and mortality and obesity may increase this risk. Indeed, when challenged with influenza virus, obese mice exhibit a decreased immune response to influenza infection leading to increased morbidity and mortality. Memory CD8+ T cells generated during primary influenza infection target internal proteins common among influenza viruses, making them effective against encounters with heterologous strains. Since previous studies in our laboratory have shown that diet-induced obese mice have a significantly altered primary immune response to influenza infection, we hypothesized that obese mice would have an impaired memory CD8+ T cell response to secondary influenza infection. In male, diet-induced obese C57Bl/6 mice, a secondary H1N1 influenza challenge following a primary H3N2 infection led to a 25% mortality rate (with no loss of lean controls), 25% increase in lung pathology, failure to regain weight and 10 to 100 fold higher lung viral titers. Furthermore, mRNA expression for interferon gamma (IFN-gamma) was >60% less in lungs of obese mice along with one third the number influenza-specific CD8+ T cells producing IFN-gamma post secondary infection versus lean controls. Memory CD8+ T cells from obese mice had a >50% reduction in IFN-gamma production when stimulated with influenza-pulsed dendritic cells from lean mice. In addition, maintenance of influenza-specific memory T cells was impaired in obese mice with a 10% reduction in this population 84 days post primary infection. Thus, the function and maintenance of influenza-specific memory T cells is significantly reduced and ineffective in lungs of obese mice. The reality of a worldwide obesity epidemic combined with yearly influenza outbreaks and the current threat of an H1N1 pandemic makes it imperative to understand how influenza virus infection behaves differently in an obese host. Moreover, impairment of memory responses has significant implications for vaccine efficacy in an obese population.