调节性 T 细胞 (Treg) 是控制免疫反应的核心，其功能失调可能导致自身免疫性疾病或癌症。尽管对 Tregs 进行了广泛的研究，但人类 Treg 发育和功能的表观遗传调控基础尚不完全清楚。长基因间非编码 RNA (lincRNA) 对于塑造和维持不同细胞类型的表观遗传景观非常重要。在这项研究中，我们鉴定了染色体 6p25.3 基因座上的一个基因，编码 lincRNA，该基因在人类 Tregs 的早期分化过程中上调。 lincRNA调节白细胞介素2受体α（IL2RA）的表达，我们将其命名为IL2RA的lincRNA调节因子（LIRIL2R）。通过对 LIRIL2R 缺陷型 Tregs 进行转录组学、表观基因组学和蛋白质组学分析，再加上通过 RNA 纯化进行染色质分离对 LIRIL2R 结合位点进行全局分析，然后进行测序，我们将 IL2RA 确定为 LIRIL2R 的靶标。这种核 lincRNA 结合 IL2RA 基因座的上游并调节其表观遗传景观和转录。 CRISPR 介导的 IL2RA 基因座 LIRIL2R 结合区的缺失导致 IL2RA 表达减少。值得注意的是，LIRIL2R 缺陷导致 Treg 特征基因（例如 FOXP3、CTLA4 和 PDCD1）表达减少、效应 T 细胞相关基因（例如 SATB1 和 GATA3）上调以及 Treg 介导的抑制作用丧失。

Regulatory T cells (Tregs) are central in controlling immune responses, and dysregulation of their function can lead to autoimmune disorders or cancer. Despite extensive studies on Tregs, the basis of epigenetic regulation of human Treg development and function is incompletely understood. Long intergenic noncoding RNAs (lincRNA)s are important for shaping and maintaining the epigenetic landscape in different cell types. In this study, we identified a gene on the chromosome 6p25.3 locus, encoding a lincRNA, that was up-regulated during early differentiation of human Tregs. The lincRNA regulated the expression of interleukin-2 receptor alpha (IL2RA), and we named it the lincRNA regulator of IL2RA (LIRIL2R). Through transcriptomics, epigenomics, and proteomics analysis of LIRIL2R-deficient Tregs, coupled with global profiling of LIRIL2R binding sites using chromatin isolation by RNA purification, followed by sequencing, we identified IL2RA as a target of LIRIL2R. This nuclear lincRNA binds upstream of the IL2RA locus and regulates its epigenetic landscape and transcription. CRISPR-mediated deletion of the LIRIL2R-bound region at the IL2RA locus resulted in reduced IL2RA expression. Notably, LIRIL2R deficiency led to reduced expression of Treg-signature genes (e.g., FOXP3, CTLA4, and PDCD1), upregulation of genes associated with effector T cells (e.g., SATB1 and GATA3), and loss of Treg-mediated suppression.