CHAF1b调控NKT细胞早期分化的作用机制

Immune system is maintained by the interaction of diverse immune cells involving in the innate and adaptive immunity. Natural killer T cells (NKT cells) can rapidly produce copious levels of cytokines to activate different immune cells after stimulation by antigen. Thus, NKT cells play important roles in the course of diseases and participate in many diseases. A lot of studies have reported that the development and functional maturation of NKT cells are largely depended on the transcriptional regulation. CHAF1b, a key subunit of the chromatin assembly factor (CAF1) complex, influences transcription through regulating the opening of chromatin at specific sites. To explore the roles of CHAF1b in NKT cells, we generated Chaf1b conditional knockout mice which Chaf1b is specifically deleted in T cells. Our primary data showed that CHAF1b deficiency did not impair conventional T cell development in thymus, but decreased the frequency and cell number of NKT cells and completely blocked the NKT cell development at stage 0. Based on this mouse model, our project will further focus on the mechanisms of CHAF1b regulating the early developmental process and functional maturation of NKT cells. This research will reveal not only the new functions of CHAF1b, but also the novel mechanisms of NKT cell fate decision which are essential in regulating the pathological function of NKT cells.

免疫系统的正常运转离不开固有免疫细胞和适应性免疫细胞间的相互作用。NKT细胞在受到抗原刺激后能快速产生大量细胞因子从而激活多种免疫细胞，在众多疾病的进程中发挥重要调控作用。多个报道表明，其分化过程与功能的获得离不开基因的转录调控。CHAF1B是染色体组装因子的一个重要亚基，它通过调控染色体特定区域的开放程度影响细胞的转录过程。为了研究CHAF1b在NKT细胞分化和功能成熟过程中的作用，我们构建了在T细胞中敲除Chaf1b的小鼠模型，初步研究结果表明，CHAF1b的缺失不影响传统T细胞在胸腺内的分化，但NKT细胞的比例和数目出现显著下降，其分化进程显著停滞在阶段0。鉴于此，本项目将以该小鼠为模型，深入研究CHAF1b调控NKT细胞早期分化以及功能成熟的分子机制。该研究将揭示CHAF1b的新功能，NKT细胞命运决定过程中的新机制，为调控NKT细胞在疾病中的作用提供新线索。

NKT细胞在受到抗原刺激后能快速产生大量细胞因子，从而激活固有免疫和适应性免疫细胞，在炎症和肿瘤的进程中发挥重要的调控作用。我们项目的研究结果表明，敲除染色体组装因子亚基Chaf1b后，损害NKT细胞的早期分化，但不影响传统T细胞的分化，维持了NKT细胞功能的获得。我们的工作首先证明了CHAF1b通过调控Vα14-Jα18 的染色体活性以及转录表达，调控NKT细胞谱系的决定。其次，证明了CHAF1b是NKT细胞早期分化的特异性调控子，CHAF1b不影响传统T细胞分化，对于NKT细胞引发的肝脏炎症以及肿瘤中的作用无显著调控作用。本研究不仅揭示了CHAF1b调控NKT细胞谱系决定的关键分子机制，而且证明了CHAF1b对于NKT细胞早期分化的特异性调控作用，以及TCR信号在其中的重要性，为理解NKT细胞的分化与功能的发挥提供重要的理论基础。