The function of the immune system changes profoundly with age. One of the most clinically important changes is that vaccine efficacy significantly declines in the elderly, leaving them more susceptible to infectious diseases such as influenza and pneumonia. This decline leads to lower overall antibody (Ab) titers as well as reduced Ab function. In addition, aging individuals have an increased incidence of inflammation and chronic inflammatory infections, both of which can potentially have a significant impact on the outcome of a primary immune response. We currently do not know whether the increased incidence of inflammation and infection in the elderly contributes to their reduced ability to respond to infection and vaccination. In this regard we have generated two sets of data that have prompted us to pursue this issue in this R21 application. Using a novel adoptive transfer model with T cell receptor transgenic (TCR Tg) CD4 T cells, we have shown that naive CD4 T cells from aged individuals exhibit a reduced ability to promote Ab responses to vaccination compared to young CD4 T cells. In addition, in the preliminary data, we show that aged hosts express an increased frequency of cells capable of producing the inflammatory cytokine IL-17, and that this frequency is further increased by the presence of mycobacterial infection. These observations prompted us to propose the hypothesis that the priming and cognate function of CD4 T cells is influenced by chronic infection and that age of both T cells and host exacerbate this influence. To test this hypothesis, we have outlined 4 aims that will determine the impact of infection and inflammation on the CD4 T cell response to vaccination.
Aim 1. To what extent does chronic infection in the aged host influence the priming of young naive CD4 T cells? Aim 2. To what extent does chronic infection influence the priming of aged CD4 T cells? Aim 3. To what extent does chronic infection influence the cognate helper function of aged CD4 T cells? Aim 4. To what extent does chronic infection influence the development and expression of CD4 T cell memory? We will use TCR Tg T cells to provide sufficient numbers of uniform naive T cells and a low-virulence yet inflammatory mycobacterial infection (BCG) to provide a reproducible increase in the level of inflammation in both young and aged hosts. We can follow both T and B cell responses to vaccination allowing us to determine the extent to which infection modulates the response of both sets of cells. These experiments are relevant to human health since determining the effect of inflammation on the response to vaccination will allow us to improve vaccination in the elderly. ? ? ? ?
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