State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, P. R. China.
School of Life Science and Technology, Shanghai Tech University, Shanghai, P. R. China.
Eur J Immunol. 2021 Jul;51(7):1698-1714. doi: 10.1002/eji.202049074. Epub 2021 May 20.
CD4 CD8 double-positive thymocytes give rise to both conventional TCRαβ T cells and invariant natural killer T cells (iNKT cells), but these two kinds of cells display different characteristics. The molecular mechanism underlying iNKT cell lineage development and function acquisition remain to be elucidated. We show that the loss of chromatin assembly factor 1B (CHAF1b) maintains the normal development of conventional TCRαβ T cells but severely impairs early development of iNKT cells. This dysregulation is accompanied by the impairment in chromatin activation and gene transcription at Vα14-Jα18 locus. Notably, ectopic expression of a Vα14-Jα18 TCR rescues Chaf1b-deficient iNKT cell developmental defects. Moreover, cytokine secretion and antitumor activity are substantially maintained in Vα14-Jα18 TCR transgene-rescued Chaf1b-deficient iNKT cells. Our study identifies CHAF1b as a critical factor that controls the early development but not function acquisition of iNKT cells via lineage- and stage-specific regulation.
CD4 CD8 双阳性胸腺细胞既能产生常规 TCRαβ T 细胞，也能产生固有自然杀伤 T 细胞（iNKT 细胞），但这两种细胞表现出不同的特征。iNKT 细胞谱系发育和功能获得的分子机制仍有待阐明。我们发现，染色质组装因子 1B（CHAF1b）的缺失能维持常规 TCRαβ T 细胞的正常发育，但严重损害 iNKT 细胞的早期发育。这种失调伴随着 Vα14-Jα18 基因座上染色质激活和基因转录的损害。值得注意的是，Vα14-Jα18 TCR 的异位表达可挽救 Chaf1b 缺陷型 iNKT 细胞发育缺陷。此外，在 Vα14-Jα18 TCR 转基因拯救的 Chaf1b 缺陷型 iNKT 细胞中，细胞因子分泌和抗肿瘤活性得到了很好的维持。我们的研究确定 CHAF1b 是一个关键因素，通过谱系和阶段特异性调控，控制 iNKT 细胞的早期发育，但不控制其功能获得。
