Reprogramming of tissue structural cells by cutaneous CD4+ T cells

项目总结/摘要 虽然长期以来被认为是适应性细胞如T和B细胞的独特特征，但现在清楚的是， 结构细胞也可以以稳定的表观遗传方式对先前的炎症反应进行“记忆”， 在随后的组织损伤后改变其转录潜力和行为的修饰，以及 这被称为“炎症性记忆”。这凸显了我们对T细胞-组织交叉知识的关键差距 这是该提案试图解决的问题。这个提议的前提是皮肤T细胞局部重编程， 角质形成细胞和成纤维细胞在炎症过程中，从而改变其转录和表观遗传 景观，功能和对后续刺激的反应，这影响了课程和解决方案， 炎症性皮肤病。为了填补这些关键的知识空白，我们将研究T细胞和 创新细胞培养系统中的结构细胞，以监测细胞行为和功能的变化，以及 机械地将它们与T细胞衍生的细胞因子的转录和表观遗传重编程联系起来。我们将 还利用已建立的高度可操作的T细胞依赖性皮肤炎症小鼠模型， 检查体内KCs和Fib中炎症记忆的发展， 重要的细胞因子和表观遗传介质，并评估功能后果，对后续 炎症和组织修复反应。最后，我们将分析组织中炎症记忆的特征， 来自患有常见皮肤炎性疾病银屑病和特应性皮炎的患者的样品，和 在临床前模型中评估表观遗传重编程作为一种新的治疗方式来重置炎症 并打破这些患者皮肤中的炎症循环。

Project Summary/Abstract Although long thought to be a unique feature of adaptive cells such as T and B cells, it is now clear that tissue structural cells can also harbor ‘memory’ of prior inflammatory responses in the form of stable epigenetic modifications that alter their transcriptional potential and behavior following subsequent tissue damage, and this is referred to as ‘inflammatory memory’. This highlights key gaps in our knowledge of T cell-tissue cross- talk that this proposal seeks to address. The premise of this proposal is that cutaneous T cells reprogram local keratinocytes and fibroblasts during inflammation, thereby altering their transcriptional and epigenetic landscape, function, and responses to subsequent stimuli, and that this influences the course and resolution of inflammatory skin disease. To fill these key knowledge gaps, we will examine the cross-talk between T cell and structural cells in innovative cell culture systems to monitor changes in cell behavior and function, and mechanistically link them to transcriptional and epigenetic reprogramming by T cell-derived cytokines. We will also leverage an established and highly manipulatable murine model of T cell-dependent skin inflammation to examine the development of inflammatory memory in KCs and Fibs in vivo, to mechanistically identify important cytokines and epigenetic mediators, and to assess the functional consequences on subsequent inflammatory and tissue-repair responses. Finally, we will analyze signatures of inflammatory memory in tissue samples from patients with the common skin inflammatory diseases psoriasis and atopic dermatitis, and assess epigenetic reprogramming in a preclinical model as a new therapeutic modality to reset inflammatory memory and break the inflammatory cycle in the skin of these patients.