The State of T Cell Immunity against Influenza Virus in Humans and Exploration of Potential Strategies to Enhance Cell-Mediated Protection from Influenza Infection

There is great interest in developing a broadly efficacious influenza vaccine, as current antibody-eliciting formulations require annual re-immunization and are not effective in those most susceptible to influenza-related mortality. In contrast to antibody responses, influenza-specific CD8 T cells are broadly cross-reactive between strains, and previous reports have indicated that cellular immunity is a better correlate of protection than neutralizing antibody titers. However, little is known about the state of influenza-specific cellular immunity in humans. To address this, we examined the CD8 T cell responses of humans of different age, vaccination, and infection history to determine whether any of these factors alter the functionality of cell-mediated immune memory. We identified distinct phenotypic changes in influenza-specific T cells from older subjects, which were predictive of their antibody responses upon influenza vaccination. However, the inactivated vaccine itself had no discernible immediate or persisting effects on influenza-specific CD8 T cell responses of young or old humans. Furthermore, adults (mean age 44) who acquired natural influenza infections of the 2009 pandemic strain also had similar influenza-specific CD8 T cell responses 8-10 months after infection compared to controls. From these results, we concluded that influenza infection and vaccination do not result in significant long-term boosting of pre-existing influenza-specific CD8 T cell responses and that a lifetime of acute influenza infections can result in a senescent phenotype similar to chronically stimulated dysfunctional cells. These data suggested that boosting functional influenza-specific CD8 T cells in middle age that endure into old age could enhance protection in the elderly. To test this, we evaluated a murine prime/boost model using the 4-1BB costimulatory pathway to induce persisting CD8 T cell responses. 4-1BBL signals during boost immunization resulted in superior numbers and function of persisting influenza-specific CD8 T cells. Since TRAF1, an adaptor molecule for 4-1BB signaling, is polymorphic in humans, a preliminary investigation was undertaken to assess the effect of TRAF1 polymorphisms on T cell responses. Although a range of TRAF1 expression was detected, all donors exhibited enhanced T cell activation with anti-4-1BB, suggesting that targeting this pathway has therapeutic potential in a human T cell-stimulating influenza vaccine.Ph