Visualizing, Quantifying, and Modeling of T Cell Response to Listeria Infection

Listeria monocytogenes is an intracellular bacterial pathogen that causes severe infections inimmunosuppressed hosts. In normal hosts L. monocytogenes is cleared by a robust T cell responseincluding both CDS and CD4 populations. CD4 T cells contribute to isolation of the bacteria in granulomasand killing through macrophage activation, whereas CD8 T cells give rise to cytotoxic T lymphocytes thatdirectly kill infected host cells. The priming of naive L. monocytogenes specific T cells is limited to the firstfew days of infection and ends once active CTL are produced, leading to the hypothesis that CTL mediatedkilling of antigen presenting dendritic cell prevents further priming of naive T cells.<P> Two photon laserscanning microscopy has generated vivid images of T cell migration in lymph nodes and provided insight intohow dendriic cells with antigen come into contact with rare antigen specific naive T cells. The stochasticrepertoire scanning hypothesis states that naive T cells migrate rapidly and randomly in through T cell zonescontaining networks of DC extending long dendrites such that each dendritic cell contacts 5000 T cells perhour. Simulations based on theoretical models of glass forming liquids suggest that the optimal searchstrategy for naive T cells interaction with antigen positive DC is to have short range attractions with theoptimal range of attraction dependent upon the number of infected ARC. We will use simulations fromtheory and experiments to better understand the search of naive T cells for antigen positive APC in vivo andthe consequences of the containment or spread of infection in the host.<P> In Aim 1 we will use computationsmethods and experimentation to determine the optimal and actual search strategy at the priming and effectorphases of the CD4 and CDS responses.<P> In Aim 2 we will test the role of dendritic cells in T cell priming anddetermine how reduction in dendritic cell numbers alters CD4 and CDS T cell activation and signalintegration in vivo.<P> In Aim 3 we will develop models for L. monocytogenes growth in the organism andcontrol by CD4 and CDS T cell responses and perform experiments to complement published data on thenatural history of the infection.<P> The results will provide quantitative insights into the adaptive immuneresponse to L. monocytogenes that may lead to improved vaccination strategies and paradigms.