T cell reactivation in acute kidney injury

淋巴细胞效应反应是炎症过程的一个标志。过去的研究已经证实，CD4T细胞在缺血再灌注介导的肾脏损伤和肾小球肾炎中都起着至关重要的作用。然而，组织中这些细胞的重新激活是必要的，以激发它们的生物学功能。本研究的目的是描述急性肾损伤模型组织中效应性T细胞的再激活过程。首先，我们的目标是确定负责组织再激活的抗原提呈细胞(而不是介导启动的树突状细胞)。在此背景下，我们将使用一种新的基于流式细胞仪的方法来研究缺血-再灌注损伤后的体内细胞结合物，以及已建立的具有已知抗原的肾小球肾炎模型。此外，我们还将研究CD4T细胞在建立临床相关的脓毒症所致肾损伤模型中的作用。其次，将利用RNAseq技术分析重新激活的T细胞的转录组。为此，将对重新激活的T细胞的不同特征进行评估和关联，以识别重新激活的T细胞。这一转录组分析的结果将在缺血-再灌注损伤、败血症引起的肾脏损伤和肾小球肾炎中进行检验，此外，还将检查它们对共刺激分子的依赖性，以及它们与已知涉及T细胞耗竭的分子的关系。第三，将通过抗体耗竭研究和先前报道的髓系细胞募集受损但T细胞募集完好的基因敲除小鼠来检验髓系细胞在组织中重新激活的重要性。

Lymphocyte effector responses are a hallmark of inflammatory processes. Past studies have identified CD4 T cells to be crucially involved in both ischemia-reperfusion mediated kidney injury and glomerulonephritis. However, reactivation of these cells in the tissue is necessary to elicit their biological function. The aim of this study is to characterize the reactivation process of effector T cells in the tissue in models of acute kidney injury. First, we aim to identify the antigen presenting cell responsible for tissue reactivation (as opposed to dendritic cells that mediate priming). In this context we will use a novel FACS based approach to investigate in vivo cell conjugates following ischemia-reperfusion injury and an established glomerulonephritis model with a known antigen. Furthermore, we will examine the role of CD4 T cells in the development of a clinically relevant sepsis induced kidney injury model. Secondly, the transcriptome of reactivating T cells will be analyzed using RNAseq technology. For this purpose, different characteristics of reactivating T cells will be assessed and correlated to identify reactivated T cells. The results of this transcriptome analysis will then be examined in ischemia-reperfusion injury, sepsis induced kidney injury and glomerulonephritis and, in addition, in their dependency on costimulatory molecules and their association with molecules known to be involved in T cell exhaustion. Thirdly, the importance of myeloid cells for reactivation in the tissue will be examined using antibody depletion studies and knockout mice previously reported to have impaired myeloid cell recruitment but intact T cell recruitment.