Examining the Aged Immune System: Elucidating the Underlying Mechanisms That Promote More Effective Influenza Responses and Regulate CD4 T Cell Subsets

Aging greatly contributes to increased susceptibility to influenza infection. To effectively protect against influenza-related complications and mortality, a robust, yet controlled, cellular and humoral immune response is critical. CD4 T cells aid in carefully orchestrating the balance between inflammatory and anti-inflammatory influenza responses. With this research, we examine how the aged environment impacts these responses and CD4 T cell differentiation following influenza infection in aged mice. In this thesis, we show that the aging environment compromises the ability of CD4 T cells to differentiate into functional subsets, resulting in a multitude of dysregulated responses including, delayed viral clearance and prolonged inflammation. Priming CD4 T cells using vaccination, however, can significantly reduce inflammation, increase survival, and promote a balance between inflammatory CD4 T cell subsets. There is a significant reduction in TGF-bwith vaccination, which reduces the amount of regulatory CD4 T cells in aged mice, necessary to have an effective inflammatory response. TGF-breduction by neutralization reduces IFN-gin aged mice after infection. Even further, we examine how inflammatory and regulatory CD4 T cells are affected after eliminating senescent cells, major contributors to the aged environment. Using the senolytic cocktail D+Q, regulatory CD4 T cells and TGF-bare reduced, suggesting that the senescent environment could be effecting CD4 T cell responses to influenza. This research is the first examine the relationship between senescence and CD4 T cell differentiation. Collectively, this research shows the aged environment can be overcome to promote regulated influenza responses with aging