The Role of Cytoplasmic and Nuclear THEMIS in Immature and Mature T cells

摘要 Themis与人类越来越多的炎症性疾病有关，包括乳糜泻， 多发性硬化症和特应性皮炎。Themis相关性疾病影响不同的解剖部位和 遵循不同的发病机制，将THEMIS定位为核心的“炎症”控制因素之一。尽管强者 THEMIS与人类多种炎症性疾病及T细胞深度缺陷的关系 THEMIS缺陷小鼠的发育和选择、THEMIS的功能及其途径或因素 与之互动仍是个谜。THEMIS1在T细胞中表达，在那里它作为下游的关键接头发挥作用 TCR的一部分。在胸腺细胞中，阳性选择是导致幼稚T细胞产生的关键。Themis 继续在成熟的CD8ab和CD4TCRab T细胞中表达，但其在成熟T细胞中的作用尚不清楚。 此外，THEMIS在细胞核和细胞质中都有表达，尽管THEMIS作为TCR 适配器，已经得到了很好的研究，它在核中的作用仍然不确定，对它的研究也一无所知 这种不同的亚细胞定位对其在胸腺细胞或成熟T细胞中的功能的意义。这些 我们对THEMIS生物学的了解存在重大差距，这极大地阻碍了识别 THEMIS在与其相关的疾病中的作用或设计有效的战略来针对THEMIS 治疗炎症性疾病或加强对感染和癌症的保护。这里的建议是 着手通过使用独特的新工具来检查细胞质中的THEMIS来解决这些显著的差距 未成熟T细胞和成熟T细胞的核。

Abstract THEMIS associates with a growing number of inflammatory diseases in humans, including Celiac Disease, Multiple Sclerosis and Atopic Dermatitis. THEMIS associated disorders affect different anatomical sites and follow different pathogeneses, placing THEMIS as one of the core “inflammatory”-controllers. Despite the strong association of THEMIS with multiple inflammatory diseases in humans and the profound defects in T cell development and selection in THEMIS-deficient mice, the function of THEMIS and the pathways or factors it interacts with remain enigmatic. THEMIS1 is expressed in T cells where it functions as a key adaptor downstream of the TCR. In thymocytes it is essential for positive selection leading to the generation of naïve T cells. THEMIS continues to be expressed in mature CD8ab and CD4 TCRab T cells but its role in mature T cells is not known. Moreover, THEMIS is expressed in the nucleus as well as in the cytoplasm and although THEMIS, as a TCR adaptor, has been well studied, it’s role in the nucleus remains undefined and nothing is known about the significance of this differential subcellular localization for its function in thymocytes or mature T cells. These significant gaps in our understanding of the biology of THEMIS greatly impede on the progress to identify the role of THEMIS in those diseases it is associated with or to design effective strategies to target THEMIS for the treatment of inflammatory diseases or to enhance protection against infections and cancers. The proposal here sets out to address these significant gaps with the use of unique new tools to examine THEMIS in the cytoplasm and nucleus of immature and mature T cells.