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Foxp3DEx2 isoform expression leads to Treg dysfunction and SLE

Foxp3DEx2 同工型表达导致 Treg 功能障碍和 SLE

基本信息

批准号：
10363690
负责人：
Steven F Ziegler
金额：
$ 21.76万
依托单位：
BENAROYA RESEARCH INST AT VIRGINIA MASON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-03 至 2023-08-31
项目状态：
已结题

项目摘要

Project Summary Regulatory T (Treg) cells play a central role in maintaining immune system homeostasis and modulating immune responses. Foxp3 is a master regulator of Treg development and function. FOXP3 mutations in patients with IPEX, which result in a deficiency in Tregs, result in lethal autoimmunity, similar to the disease observed in Foxp3 deficient mice. While highly conserved in both amino acid sequence and gene structure, one difference between humans and mice is that the human FOXP3 gene encodes two major alternatively spliced isoforms: a full length version that uses all 10 exons (FOXP3-FL, the only isoform in mice) and a shorter isoform lacking sequences shown to be important in regulating Th17 differentiation. Recent studies have shown that Tregs from patients with some autoimmune diseases express increased levels of the ∆E2 isoform compared to those from healthy donors. Consistent with this finding, we have found that Tregs from SLE patients have increased expression of the FOXP3∆Ex2 isoform. To study the role of the ∆E2 isoform in Treg function we generated a new mouse strain with Foxp3 exon 2 deletion. Interestingly, we found that Foxp3∆E2 mice develop hallmark features of SLE, including anti- DNA and anti-nuclear autoantibodies, increased number and size of spontaneous germinal centers and kidney deposition of antibody complexes, by 4-5 weeks of age. However, these mice do not develop full-blown disease and have a normal life span. Our central hypothesis is that the region encoded by exon 2 of Foxp3 gene is critical for normal Treg identity and function. To test this hypothesis we will take 2 approaches. First, we will determine the levels of FOXP3-FL and -∆Ex2-expressing Tregs in healthy human subjects and subjects with autoimmune disease. These studies will be complemented with studies using mice containing varying ratios of Tregs expressing each isoform. Second, we test the hypothesis that Tregs expressing FOXP3-∆Ex2 have a reduced ability to regulate effector T cell activation, using both human Treg clones and a mouse transfer colitis model. Together these studies will allow us to gain important information on the expression of FOXP3∆Ex2 and the function of Tregs expressing this isoform.

项目摘要调节性T(Treg)细胞在维持免疫系统动态平衡和调节免疫反应。Foxp3是Treg发育和功能的主要调节因子。Foxp3 IPEX患者的突变导致Tregs缺陷，导致致命性自身免疫，类似于在Foxp3缺陷小鼠身上观察到的这种疾病。在氨基酸序列和基因上都高度保守结构上，人和小鼠的一个不同之处是，人的FOXP3基因编码两个主要的选择性剪接异构体：使用全部10个外显子的全长版本(FOXP3-FL，小鼠唯一的异构体) 而缺乏序列的较短的异构体在调节Th17分化中起重要作用。近期研究表明，某些自身免疫性疾病患者的Tregs表达水平升高 ∆E2亚型与健康献血者的比较。与这一发现一致的是，我们发现特雷格斯来自系统性红斑狼疮患者的FOXP3∆EX2亚型表达增加。为了研究∆E2亚型在Treg功能中的作用，我们用Foxp3产生了一个新的小鼠品系外显子2缺失。有趣的是，我们发现FOXP3∆E2小鼠出现了系统性红斑狼疮的特征，包括抗- DNA和抗核自身抗体，自发性生发中心和肾脏的数量和大小增加 4-5周龄时抗体复合体沉积。然而，这些小鼠并没有发育成熟。并拥有正常的寿命。我们的中心假设是由外显子2编码的区域 Foxp3基因对Treg的正常识别和功能至关重要。为了检验这一假设，我们将采用2 接近了。首先，我们将测定在健康人中FOXP3-FL和-∆EX2的表达水平受试者和自身免疫性疾病的受试者。这些研究将与用小鼠进行的研究相辅相成含有不同比例的表达每种异构体的Tregs。其次，我们检验了Tregs的假设表达FOXP3-∆EX2降低了调节效应T细胞激活的能力克隆和小鼠转移结肠炎模型。总之，这些研究将使我们能够获得重要的信息 FOXP3∆EX2的表达及表达该异构体的Tregs的功能