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Abstract：
While the transcription factor GATA-3 is well-established for its crucial role in T cell development, its specific influence on invariant natural killer T (iNKT) cells remains relatively unexplored. Using flow cytometry and single-cell transcriptomic analysis, we demonstrated that GATA-3 deficiency in mice leads to the absence of iNKT2 and iNKT17 cell subsets, as well as an altered distribution of iNKT1 cells. Thymic iNKT cells lacking GATA-3 exhibited diminished expression of PLZF and T-bet, key transcription factors involved in iNKT cell differentiation, and reduced production of Th2, Th17, and cytotoxic effector molecules. Single-cell transcriptomics revealed a comprehensive absence of iNKT17 cells, a substantial reduction in iNKT2 cells, and an increase in iNKT1 cells in GATA-3-deficient thymi. Differential expression analysis highlighted the regulatory role of GATA-3 in T cell activation signaling and altered expression of genes critical for iNKT cell differentiation, such as Icos, Cd127, Eomes, and Zbtb16. Notably, restoration of Icos, but not Cd127, expression could rescue iNKT cell development in GATA-3-deficient mice. In conclusion, our study demonstrates the pivotal role of GATA-3 in orchestrating iNKT cell effector lineage differentiation through the regulation of T cell activation pathways and Icos expression, providing insights into the molecular mechanisms governing iNKT cell development and function.
摘要：
虽然转录因子GATA-3在T细胞发育中起关键作用，其对不变自然杀伤T(iNKT)细胞的特定影响仍未被探索。使用流式细胞术和单细胞转录组学分析，我们证明，小鼠GATA-3缺乏导致iNKT2和iNKT17细胞亚群的缺失，以及iNKT1细胞分布的改变。缺乏GATA-3的胸腺iNKT细胞表现出PLZF和T-bet的表达减少，参与iNKT细胞分化的关键转录因子，减少Th2、Th17和细胞毒性效应分子的产生。单细胞转录组学显示iNKT17细胞的全面缺失，iNKT2细胞的大量减少，以及GATA-3缺陷胸腺中iNKT1细胞的增加。差异表达分析强调了GATA-3在T细胞活化信号传导和对iNKT细胞分化至关重要的基因表达改变中的调节作用。比如Icos,Cd127，Eomes，Zbtb16值得注意的是,Icos的恢复,而不是Cd127，表达可以挽救GATA-3缺陷小鼠的iNKT细胞发育。总之,我们的研究证明了GATA-3在通过调节T细胞活化途径和Icos表达来协调iNKT细胞效应谱系分化中的关键作用，提供对控制iNKT细胞发育和功能的分子机制的见解。
