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

Massachusetts Institute Of Technology, Cambridge MA

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Abstract

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