自身免疫调节因子AIRE通过上调HEXIM1促进T细胞中枢免疫耐受的机制研究

自身免疫调节因子AIRE在胸腺髓质上皮细胞(mTEC)中调控组织特异性抗原的异位表达并最终诱导mTEC凋亡，以促进树突状细胞吞噬mTEC及组织特异性抗原呈递，但其诱导凋亡机制不清楚。有报道：HEXIM1是转录抑制因子，也可调控细胞凋亡。我们发现：AIRE可以上调HEXIM1表达；HEXIM1敲除后AIRE无法诱导凋亡基因表达。推测：HEXIM1可能调控AIRE介导的T细胞中枢免疫耐受。为此，我们将探索AIRE上调HEXIM1机制；制备HEXIM1胸腺特异性敲除小鼠；通过单细胞测序检测HEXIM1敲除后胸腺发育及免疫微环境变化等实验探索AIRE调控HEXIM1促进mTEC凋亡分子机制；揭示HEXIM1在mTEC分化发育中的作用。上述研究内容均属原始创新，该研究对进一步阐明中枢免疫耐受形成机制以及操控免疫耐受治疗自身免疫性疾病奠定新的基础。

The autoimmune regulator (AIRE) is a transcription factor which is expressed in medullary thymic epithelial cells (mTECs). It directs the expression of otherwise tissue-specific antigens (TSAs), which leads to the elimination of autoreactive T cells during development. AIRE drives negative selection of self-recognizing T cells. In this way, AIRE plays an important role in the induction of central tolerance. Researchers found that AIRE induces the apoptosis of mTECs, but its mechanism is still under unclear. Hexamethylene bisacetamide inducible 1 (HEXIM1) is a transcription suppressor and could induce apoptosis in many ways. In our previews study, we found that AIRE can up-regulate the expression of HEXIM1; In HEXIM1 knock out cells, AIRE can’t induce the expression of apoptotic genes. Therefore, we hypothesis that HEXIM1 could be a regulator of AIRE induced central tolerance, and also autoimmune diseases. To verify these hypotheses, the mechenism of AIRE upregulate HEXIM1 will be investigate; mice specifically knock out HEXIM1 gene in thymus will be generated. The roles of HEXIM1 in mTEC differentiation and central tolerance will be examed; Single cell sequencing, transcriptome RNA sequencing, bioinformatics, FACS and also other molecular and biochemical technologies will be performed to reveal the mechanism of AIRE induce apoptosis by HEXIM1.This study is an original research,and will benifite the mechanical studies of central tolerance, autoimmune diseases and also will help to discover the new treatment.