Proinflammatory Cytokines Block T Cell Death In Vivo

描述（由申请人提供）：天然佐剂细菌脂多糖（LPS）是一种促炎因子，可使T细胞规避免疫耐受。尽管破坏T细胞耐受性的机制尚不清楚，但最近的许多研究将先天免疫和适应性免疫联系起来，表明产生性免疫反应是这些相互作用的结果。LPS注射到小鼠体内可以阻止ag特异性T细胞的缺失，从而导致具有强效回忆反应的长寿命记忆T细胞的发育。我们已经提出，通过LPS规避T细胞缺失与先天免疫的激活有关，其中树突状细胞（DCs）起着重要作用。首先，这可能是通过细胞因子的作用，我们最近的研究表明，促炎细胞因子IL-18可能是防止T细胞缺失的核心。将系统地测试DCs、IL-18和MyD88分子的直接作用，它们连接先天免疫和适应性免疫的各个方面。其次，当暴露于破坏T细胞耐受性的促炎条件下时，特异性T细胞在克隆扩增之前很难从淋巴组织中去除。具体来说，ag反应性T细胞被捕获，流式细胞术几乎无法检测到，尽管它们可以通过免疫组织化学原位检测到。我们提出实验来验证诱捕是先天免疫系统和适应性免疫系统组成部分之间信息交换的一个阶段。第三，确定lps诱导的炎症如何在细胞水平上发挥作用。我们的假设是，与接受间接炎症信号的树突状细胞相比，接受LPS直接信号的树突状细胞对ag特异性T细胞的行为可能不同。这一想法将在转基因小鼠模型中进行测试，该模型允许跟踪抗原特异性T细胞与特异性银呈递物，这些细胞可以直接对LPS产生反应，而不能。总的来说，这些研究将有助于破译LPS如何诱导微环境的变化，将T细胞耐受转化为免疫。

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.