T resident memory cells in arthritis

项目摘要 成人和儿童的炎症性关节炎通常以静止活动期为特征。 紧随其后的是疾病爆发。在任何单个患者中，相同的关节通常重复发作，在 通常在疾病早期形成，然后持续数年或数十年的模式。这个 这一理论的假设是这种“联合特定记忆”反映了T的存在 驻留记忆(TRM)细胞，其靶向代表了关节炎治疗的一种新方法。 TRM是最近被描述的长寿T细胞亚群，CD8或CD4，在皮肤中发育 和其他组织作为对组织炎症的反应，此后持续多年提供 持久的特定部位免疫力。TRM从未在关节中被描述过。我们现在有了 在人类关节炎滑膜中发现了这些细胞存在的令人信服的证据 三种正交法：单细胞RNAseq，一种新的三维滑膜培养系统， 结合飞行时间细胞术(CyTOF)和曼陀罗多维 免疫荧光成像。此外，我们已经开发或调整了三个动物模型来 为研究复发、关节特异性、T细胞依赖性建立新的小鼠系统 炎症性关节炎。 在这些初步数据的基础上，我们提出了两个具体目标。首先，我们将表演一场 人类滑膜TRM表面表型的综合特征， 调节因子、转录组和新陈代谢比较滑膜TRM和滑膜效应器记忆 T细胞和来自人类皮肤的“黄金标准”TRM。其次，我们将使用我们的动物模型来 描述TRM在一段时间内的发展和持久性；测试这些 当非抗原触发和抗原暴露时，细胞可以重新激活关节炎；以及 使用局部耗竭测试TRM靶向作为治疗持久关节特异性关节炎的新方法 心理治疗。

Project Summary Inflammatory arthritis in adults and children is often characterized by periods of quiescent activity followed by disease flares. In any individual patient, the same joints typically flare repeatedly, in a pattern that usually establishes itself early in disease and then persists for years or decades. The hypothesis of this proposal is that this “joint-specific memory” reflects the presence of T resident memory (TRM) cells, whose targeting represents a new approach to arthritis therapy. TRM are a recently-described subset of long-lived T cells, either CD8 and CD4, that develop in skin and other tissues as a response to tissue inflammation, persisting for years thereafter to provide long-lasting site-specific immunity. TRM have never been described in joints. We have now developed compelling evidence for the presence of these cells in human arthritic synovium using three orthogonal approaches: single-cell RNAseq, a novel 3-dimensional synovial culture system, coupled with cytometry by time of flight (CyTOF), and Mantra multidimensional immunofluorescence imaging. Further, we have developed or adapted three animal models to develop new murine systems optimized for the study of recurrent, joint-specific, T cell-dependent inflammatory arthritis. Building upon these preliminary data, we propose two specific aims. First, we will perform a comprehensive characterization of human synovial TRM with respect to surface phenotype, mediators, transcriptome, and metabolism to compare synovial TRM with synovial effector memory T cells and “gold standard” TRM from human skin. Second, we will use our animal models to characterize the development and persistence of TRM over time; to test the possibility that these cells can re-activate arthritis upon antigen-independent triggering as well as antigen exposure; and employ local depletion to test TRM targeting as a novel approach to durable joint-specific arthritis therapy.