Understanding the role of Id2 in T cell differentiation and activation during GVHD

摘要 骨髓移植（BMT）可以治愈各种血液恶性肿瘤，但移植物与 宿主病（GVHD），供体细胞对宿主的免疫反应，仍然是这种疾病中最致命的风险。 疗法T淋巴细胞在宿主中驱动炎症反应，这可能导致器官损伤， 破坏，甚至死亡的移植受体。虽然广泛的免疫抑制剂是为了防止 尽管GVHD的诊断和治疗都很困难，但诊断后死亡率仍高达50%。GVHD有两种形式，急性GVHD和急性GVHD。 和慢性的，它们在发育时间和病理学上不同。需要有更有针对性的 预防GVHD的治疗，同时仍然保持针对病原体的保护性免疫功能， 恶性复发我们已经使用了我们高度相关的非人灵长类动物（NHP）GVHD模型， 鉴定GVHD靶器官中T细胞上调的基因。通过转录组通路分析， 已经鉴定出DNA结合抑制剂2（ID 2）作为许多基因激活的关键上游调节剂， 在GVHD期间破坏靶器官。在文献中，Id 2参与调节T细胞分化，但 这是如何发生的以及它如何影响GVHD背景下T细胞的功能仍然是未知的。这 一个项目旨在了解T细胞中ID 2缺失如何影响其分化为1型和17型（Th/c）的能力 1和Th/c17）驱动GVHD的T细胞和预防GVHD的调节性T细胞（Treg）。我们将使用 CRISPR/Cas9首次删除1型和17型T细胞中的ID 2，并在体外和GVHD中探索其功能 模型我们还将评估ID 2编辑的T细胞的调控格局在基线时和免疫应答中的变化。 通过转录组学分析的GVHD背景。其次，我们将从Treg细胞中删除ID 2以确定 ID 2在维持其抑制活性方面的作用。我们将评估ID 2缺失的Treg细胞 以控制GVHD，特别是在cGVHD中，其中T细胞在抑制常规T细胞中起着至关重要的作用。 长期.靶向1型和17型T细胞的致病性，同时保留T调节细胞的保护作用 细胞仍然是BMT领域的一个挑战，文献表明，靶向ID 2可能会导致 宽容这个项目将是重要的，在更好地了解ID 2在T细胞分化中的作用，以及如何 以ID 2为靶点可能代表一种控制或治疗GVHD的新的治疗策略。

Abstract Bone Marrow Transplantations (BMT) can be curative for a variety of hematologic malignancies but Graft Versus Host Disease (GVHD), an immune reaction of donor cells against the host, remains the deadliest risk of this therapy. T lymphocytes drive an inflammatory response in the host that can result in organ damage and destruction, and even death of the transplant recipient. While broad immunosuppressants are given to prevent and treat GVHD, it still results in the mortality of up to 50% after diagnosis. GVHD occurs in two forms, acute and chronic, that differ in their time to development as well as pathology. There is a need for more targeted therapies to prevent GVHD, while still maintaining the protective immune functions against pathogens and malignant relapse. We have used our highly translationally relevant non-human primate (NHP) model of GVHD to identify genes upregulated in T cells in target organs of GVHD. Through transcriptomic pathway analysis we have identified inhibitor of DNA-binding 2 (ID2) as a key upstream regulator of many genes activated in the destruction of target organs during GVHD. In the literature Id2 is involved in regulating T cell differentiation, but how this occurs and how it affects the functionality of T cells in the context of GVHD remains unknown. This project aims to understand how ID2 deletion in T cells affects their ability to differentiate into Type 1 and 17 (Th/c 1 and Th/c 17) T cells which drive GVHD and regulatory T cells (Treg) which prevent GVHD. We will use CRISPR/Cas9 to first delete ID2 in type 1 and 17 T cells and explore their functionality in vitro and in GVHD models. We will also assess how the regulatory landscape of ID2-edited T cells changes at baseline and in the context of GVHD through transcriptomic profiling. Second, we will delete ID2 from Treg cells to determine the effects of id2 in maintaining their suppressive activity. And we will evaluate the ability of ID2-delteted Treg cells to control GVHD, especially in cGVHD where Tregs play a vital role in suppressing conventional T cells in the long term. Targeting the pathogenicity of type 1 and 17 T cells while sparing the protective effects of T regulatory cells remains a challenge in the BMT field and the literature suggests that targeting ID2 may tip both towards tolerance. This project will be important in understanding better the role of ID2 in T cell differentiation and how targeting ID2 may represent a novel therapeutic strategy for controlling or treating GVHD.