Listeria monocytogenes is an intracellular bacterial pathogen that causes severe infections in immunosuppressed hosts. In normal hosts L. monocytogenes is cleared by a robust T cell response including both CDS and CD4 populations. CD4 T cells contribute to isolation of the bacteria in granulomas and killing through macrophage activation, whereas CD8 T cells give rise to cytotoxic T lymphocytes that directly kill infected host cells. The priming of naive L. monocytogenes specific T cells is limited to the first few days of infection and ends once active CTL are produced, leading to the hypothesis that CTL mediated killing of antigen presenting dendritic cell prevents further priming of naive T cells. Two photon laser scanning microscopy has generated vivid images of T cell migration in lymph nodes and provided insight into how dendriic cells with antigen come into contact with rare antigen specific naive T cells. The stochastic repertoire scanning hypothesis states that naive T cells migrate rapidly and randomly in through T cell zones containing networks of DC extending long dendrites such that each dendritic cell contacts 5000 T cells per hour. Simulations based on theoretical models of glass forming liquids suggest that the optimal search strategy for naive T cells interaction with antigen positive DC is to have short range attractions with the optimal range of attraction dependent upon the number of infected ARC. We will use simulations from theory and experiments to better understand the search of naive T cells for antigen positive APC in vivo and the consequences of the containment or spread of infection in the host.
In Aim 1 we will use computations methods and experimentation to determine the optimal and actual search strategy at the priming and effector phases of the CD4 and CDS responses.
In Aim 2 we will test the role of dendritic cells in T cell priming and determine how reduction in dendritic cell numbers alters CD4 and CDS T cell activation and signal integration in vivo.
In Aim 3 we will develop models for L. monocytogenes growth in the organism and control by CD4 and CDS T cell responses and perform experiments to complement published data on the natural history of the infection. The results will provide quantitative insights into the adaptive immune response to L. monocytogenes that may lead to improved vaccination strategies and paradigms.
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