Differing from the mouse Foxp3 gene that encodes only one protein product, human FOXP3 encodes two major isoforms through alternative splicing—a longer isoform (FOXP3 FL) containing all the coding exons and a shorter isoform lacking the amino acids encoded by exon 2 (FOXP3 ΔE2). The two isoforms are naturally expressed in humans, yet their differences in controlling regulatory T cell phenotype and functionality remain unclear. In this study, we show that patients expressing only the shorter isoform fail to maintain self-tolerance and develop immunodeficiency, polyendocrinopathy, and enteropathy X-linked (IPEX) syndrome. Mice with Foxp3 exon 2 deletion have excessive follicular helper T (T FH ) and germinal center B (GC B) cell responses, and develop systemic autoimmune disease with anti-dsDNA and antinuclear autoantibody production, as well as immune complex glomerulonephritis. Despite having normal suppressive function in in vitro assays, regulatory T cells expressing FOXP3 ΔE2 are unstable and sufficient to induce autoimmunity when transferred into Tcrb -deficient mice. Mechanistically, the FOXP3 ΔE2 isoform allows increased expression of selected cytokines, but decreased expression of a set of positive regulators of Foxp3 without altered binding to these gene loci. These findings uncover indispensable functions of the FOXP3 exon 2 region, highlighting a role in regulating a transcriptional program that maintains T reg stability and immune homeostasis.

中文翻译：

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FOXP3 外显子 2 控制 T reg 稳定性和自身免疫

与鼠标不同福克斯p3只编码一种蛋白质产物的基因，即人类FOXP3通过选择性剪接编码两种主要亚型 - 包含所有编码外显子的较长亚型 (FOXP3 FL) 和缺少外显子 2 编码氨基酸的较短亚型 (FOXP3 ΔE2)。这两种亚型在人类中自然表达，但它们在控制调节性 T 细胞表型和功能方面的差异仍不清楚。在这项研究中，我们发现仅表达较短亚型的患者无法维持自身耐受性，并出现免疫缺陷、多内分泌病和 X 连锁肠病 (IPEX) 综合征。小鼠与福克斯p3外显子 2 缺失有过多的卵泡辅助 T (T跳频) 和生发中心 B (GC B) 细胞反应，并发展为具有抗 dsDNA 和抗核自身抗体产生的系统性自身免疫性疾病，以及免疫复合物肾小球肾炎。尽管在体外测定中具有正常的抑制功能，但表达 FOXP3 ΔE2 的调节性 T 细胞不稳定，当转移到体内时足以诱导自身免疫。Tcrb- 缺陷小鼠。从机制上讲，FOXP3 ΔE2 亚型允许选定细胞因子的表达增加，但一组正调节因子的表达减少福克斯p3不改变与这些基因位点的结合。这些发现揭示了 FOXP3 外显子 2 区域不可或缺的功能，强调了在调节维持 T 的转录程序中的作用。注册稳定性和免疫稳态。