Proinflammatory Cytokines Block T Cell Death In Vivo

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DESCRIPTION (provided by applicant): The natural adjuvant bacterial lipopolysaccharide (LPS) is a proinflammatory factor that conditions T cells to circumvent immunological tolerance. Although the mechanism of breaking T cell tolerance is unclear, many recent studies have linked innate and adaptive immunity suggesting that productive immune responses are a result of these interactions. LPS injection into mice prevents Ag-specific T cell deletion leading to the development of long-lived memory T cells that possess potent recall responses. We have proposed that circumvention of T cell deletion by LPS is linked to the activation of innate immunity with an important role for dendritic cells (DCs). Firstly, this may be through the action of cytokines and our recent studies suggest that the proinflammatory cytokine IL-18 may be central to preventing T cell deletion. A direct role for DCs, IL-18 and the MyD88 molecule, which links aspects of innate and adaptive immunity, will be systematically tested. Secondly, when exposed to proinflammatory conditions that break T cell tolerance, specific T cells are very difficult to remove from lymphoid tissue prior to clonal expansion. Specifically, Ag-reactive T cells are trapped and virtually undetectable by flow cytometry, even though they are detected in situ by immunohistochemistry. We propose experiments to test the idea that trapping is a stage of information exchange between components of the innate and adaptive immune systems. Thirdly, to determine how LPS-induced inflammation functions on a cellular level in vivo. Our hypothesis is that DCs receiving direct signals from LPS may behave differently towards Ag-specific T cells as opposed to DCs that receive indirect inflammatory signals. This idea will be tested in a transgenic mouse model that allows tracking of Ag-specific T cells concomitantly with specific-Ag presenters that can respond directly to LPS versus ones that cannot. Collectively, these studies will help decipher how LPS induces changes in the microenvironment to convert T cell tolerance to immunity.