The role of Nrf2 in T cell function and influenza - Despite considerable efforts toward vaccination, influenza and its complications continue to kill tens of thousands of people annually in the U.S., making it the eighth leading cause of death nationally. There is considerable interindividual variability in the immune response to influenza, which is due to the polymorphic nature of the immune system and other unidentified factors. Our preliminary data suggest that exposure to the synthetic food additive tert-butylhydroquinone (tBHQ) is one factor that can impact the effectiveness of the adaptive immune response to influenza. Our published studies demonstrate that tBHQ inhibits the differentiation of CD4 T cells into Th1 cells, a key cell type in antiviral host defense that is particularly important in the development of immunological memory to influenza. Our preliminary data indicate that tBHQ also markedly inhibits CD8 T cell function. Furthermore, we have found that mice on a tBHQ diet have a markedly impaired T cell response to influenza (A/PR/8/1934 H1N1 strain). While these studies indicate that tBHQ impairs both CD4 and CD8 T cell responses to viral pathogens, the underlying mechanism remains unknown. Elucidation of this mechanism will not only provide insight into ways to minimize the impact of diet on the response to viral pathogens, but could also reveal a novel regulatory pathway in T cells that is important for T cell polarization and function. The central hypothesis for this project is that tBHQ activates the transcription factor, Nrf2, which inhibits T-bet-dependent development of antiviral CD4 and CD8 effector T cells. This hypothesis is based in part upon our preliminary studies demonstrating that mice on a tBHQ diet have an impaired immune response to influenza. Specifically, mice exposed to tBHQ through diet, at concentrations present in human food, show a marked decrease in the production of cytokines, such as IFNγ, TNFα and IL-6, a reduction in the numbers of influenza-specific CD4 and CD8 T cells and increased viral burden. In addition to diminished primary response (i.e. first exposure to influenza), mice on a tBHQ diet also show an impaired memory response to influenza, causing much greater decrease in body weight and decreased numbers of influenza-specific CD4 and CD8 T cells. Furthermore, our in vitro studies demonstrate that robust activation of Nrf2 by tBHQ impairs CD4 and CD8 T cell function, as evidenced by decreased Th1 polarization, impaired IFNγ, IL-2 and granzyme B induction by activated CD8 T cells and diminished expression and activity of T-bet, a transcription factor that is critical for Th1 polarization and CD8 T cell effector function. We propose to test our hypothesis by 1) determining the mechanism by which activation of Nrf2 by tBHQ inhibits Th1 differentiation and the effector function of CD8 T cells, 2) determining the mechanism by which tBHQ inhibits the primary adaptive immune response to influenza and 3) identifying the role of Nrf2 in the impaired memory T cell response to influenza in tBHQ-fed mice.
