Arid1a通过调节preTCR及RORγt的表达控制T细胞早期发育

T细胞发育的调控机理精细且复杂，仍需深入研究。Arid1a通过转录调控影响肿瘤细胞周期和凋亡。我们和其他研究组同时发现，Arid1a调控T细胞早期发育，其缺失导致胸腺细胞多个阶段发育障碍。我们进一步发现：1) Arid1a缺失抑制DN细胞内TCRβ表达，过表达OT-I TCR能挽救DN3细胞发育阻滞，但不能逆转DP细胞数目；2) Arid1a缺失的DP细胞凋亡增加，RORγt转录降低，但机制不清楚。因此我们假设：Arid1a分别通过影响preTCR和RORγt表达调控DN3-DN4阶段的分化及DP细胞的存活。本研究将采用骨髓嵌合体模型证实Arid1a在T细胞发育的内在调控作用；分析Arid1a对TCRVβ多样性、Trbc1/2和preTα表达的影响；揭示Arid1a通过RORγt支持DP细胞存活的分子机制。研究结果将阐明调控T细胞胸腺发育和存活的新机制，为理解T细胞介导的免疫功能奠定基础。

The regulatory mechanisms of T cell development are delicate and complicated, and thus still need to be investigated in-depth. It has been reported that Arid1a is able to affect the cell cycle and apoptosis in tumor cells through regulating gene transcription. Our lab and another group simultaneously found that Arid1a deletion leads to a block of multiple developmental stages in the thymus. Furtherly, we found that: 1) loss of Arid1a dampened TCRβ expression in DN cells, whereas OT-I transgenic TCR could rescue the block of DN3 cells, but failed to restore the number of DP thymocytes; 2) Arid1a deficiency led to an increased apoptosis of DP thymocytes, which was accompanied by reduced RORγt transcription. However, the mechanism remains unclear. Therefore, we hypothesize that Arid1a may affect the differentiation from the DN3 to the DN4 stage, and DP cell survival by regulating preTCR and RORγt expression, respectively. This study will use bone marrow chimeric model to confirm the intrinsic role of Arid1a in thymocyte development, analyze the effect of Arid1a on TCRVβ diversity, Trbc1/2 and preTα expression, and finally uncover the molecular mechanism that Arid1a promotes DP thymocyte survival via a RORγt-dependent manner. Our findings will discover new molecular mechanisms involving T cell development and survival in the thymus, and provide new clues for better understanding T cell-mediated immune functions.