Strawberry notch homologues in T cell homeostasis and function

摘要 有效和持久的抗体反应，需要T和B细胞的微妙合作，是 对抗原的免疫反应和成功接种针对微生物感染的疫苗至关重要； 然而，在抗体反应中调节T细胞功能的机制仍不完全清楚。在……里面 此外，低丙种球蛋白血症是常见变量免疫缺陷(CVID)的标志，它可以 导致反复感染，甚至导致儿童死亡，是最常见的主要症状 成人免疫缺陷的病因在大多数患者中仍难以捉摸。通过全基因组外显子 通过测序，我们发现了草莓缺口同源物2(SBNO2)基因的错义突变。 SBNO1/2是一种保守的核蛋白，属于DExD/H RNA解旋酶家族。他们的同音异词， 草莓Notch(SNO)位于Notch/Hippo通路下游，对胚胎发育很重要， 果蝇的卵子发生和眼、翅、腿的发育。然而，SBNO1/2在 哺乳动物，特别是在免疫系统中，以及这两种蛋白质是否执行重叠的功能 几乎是未知的。我们已经产生了一种新的小鼠模型，Sbno2m/m，它含有CVID突变 内源性Sbno2基因与条件性Sbno1和Sbno2缺陷小鼠具有强劲的初步数据 从这些小鼠中，我们假设Sbno1/2是T细胞发育和发育的关键角色 功能，特别是在T细胞介导的抗体和抗病毒免疫反应中。我们将1)确定 Sbno1和Sbno2在T细胞发育和稳态中的作用，2)决定Sbno1和Sbno2的作用 Sbno2在T细胞介导的免疫反应中的作用，以及3)研究Sbno1/2- 介导的免疫调节。这项拟议中的研究有望阐明控制 T细胞的发育、动态平衡以及形成抗体和抗病毒免疫反应的功能。通过 说明Sbno1/2在T细胞中的重要性，我们将提供对T细胞潜在机制的洞察 生物学和CVID将指导免疫相关新治疗策略的开发 精神错乱。

Abstract Effective and long lasting antibody responses, which require delicate collaboration from both T and B cells, is essential for immune responses to antigens and successful vaccinations against microbial infections; however, the mechanisms that regulate T cell function in antibody responses are still not fully understood. In addition, hypogammaglobinemia is the hallmark of common variable immunodeficiency (CVID), which can result in repetitive infections and even death of children and is the most common symptomatic primary immune deficiency in adults with causal factors in most patients still elusive. Via whole genome exon sequencing, we have identified a mis-sense mutation in the Strawberry Notch homologue 2 (SBNO2) gene. SBNO1/2 are conserved nuclear proteins belonging to the DExD/H RNA helicase family. Their orthologue, strawberry notch (SNO), functions downstream of Notch/Hippo pathways and is important for embryogenesis, oogenesis, and development of the eye, wing and leg in drosophila. However, the functions of SBNO1/2 in mammals, especially in the immune system, and whether these two proteins perform overlapping functions are virtually unknown. We have generated a novel mouse model, Sbno2m/m, that harbors a CVID mutation in the endogenous Sbno2 gene and conditional Sbno1 and Sbno2 deficient mice. With strong preliminary data from these mice, we hypothesize that Sbno1/2 are critical players in T cells for their development and function, particularly in T cell-mediated antibody and anti-viral immune responses. We will 1) determine the roles of Sbno1 and Sbno2 for T cell development and homeostasis, 2) determine the role of Sbno1 and Sbno2 in T cell mediated immune responses, and 3) investigate the mechanisms underlying Sbno1/2- mediated immune regulation. The proposed studies are expected to illustrate novel mechanisms that control T cell development, homeostasis, and function to shape antibody and anti-viral immune responses. By illustrating the importance of Sbno1/2 in T cells, we will provide insight into mechanisms underlying T cell biology and CVID that will guide the development of novel therapeutic strategies against immune-related disorders.