HDAC2转录复合体调控IL-2/sIL-2R平衡介导缺血性卒中CD4+T淋巴细胞转分化的作用及机制研究

促进CD4+T淋巴细胞向神经保护型转化是缺血性卒中的重要治疗策略。我们前期临床研究发现：血浆sIL-2R升高是缺血性卒中神经功能预后的独立危险因素，IL-2/sIL-2R与淋巴细胞数量呈正相关，且比值越高患者预后越好。通过患者淋巴细胞ChIP-Seq发现：HDAC2与调控IL-2、IL-2Rα和β亚基的转录因子模体结合上调，GO富集分析发现HDAC2调控Th1、Th2、Th17和Treg转化相关通路。因此，本课题提出创新性假说：HDAC2与SP1/Egr1或TCF7L2形成转录复合体，调控脑缺血患者淋巴细胞IL-2、IL-2Rα和β亚基转录；α亚基脱落与IL-2竞争性结合IL-2R，β亚基激活下游信号通路，调控CD4+T细胞亚群分化，影响脑缺血损伤。本课题拟阐明HDAC2转录复合体调控IL-2与sIL-2R平衡的机制，为精准诱导CD4+T淋巴细胞向神经保护型转化治疗缺血性卒中提供新靶点。

Promoting the conversion of CD4 + T lymphocytes to neuroprotective type is an important treatment strategy for ischemic stroke. Our previous clinical study found that elevated plasma sIL-2R is an independent risk factor for neurological prognosis of ischemic stroke. IL-2/sIL-2R ratio is positively correlated with the number of lymphocytes and the prognosis. ChIP-Seq analysis of the peripheral lymphocytes of ischemic stroke patients found that HDAC2 was up-regulated in combination with transcription factor motifs that regulate IL-2, IL-2Rα and β subunits, and GO enrichment analysis found that HDAC2 regulates Th1, Th2, Th17 and Treg transformation-related pathways. Therefore, we proposes an innovative hypothesis: HDAC2 forms a transcription complex with SP1/Egr1 or TCF7L2 to regulate the gene expression of IL-2, IL-2Rα and β subunits in lymphocytes of ischemic stroke patients; the shedding α subunit competes with IL-2 to combine with IL-2R, and β subunit activates downstream signaling pathways, then regulates CD4+ T cell subset differentiation and affects cerebral ischemic injury. This project intends to clarify the mechanism by which HDAC2 transcription complex regulates the balance of IL-2 and sIL-2R, and provides a new target for the precise induction of CD4+ T lymphocytes into neuroprotective phenotype for ischemic stroke.