Innate-like T cell populations expressing conserved TCRs play critical roles in immunity through diverse developmentally acquired effector functions. Focusing on the prototypical lineage of invariant natural killer T (iNKT) cells, we sought to dissect the mechanisms and timing of fate decisions and functional effector differentiation. Utilizing induced expression of the semi-invariant NKT cell TCR on double positive thymocytes, an initially highly synchronous wave of iNKT cell development was triggered by brief homogeneous TCR signaling. After reaching a uniform progenitor state characterized by IL-4 production potential and proliferation, effector subsets emerged simultaneously, but then diverged toward different fates. While NKT17 specification was quickly completed, NKT1 cells slowly differentiated and expanded. NKT2 cells resembled maturing progenitors, which gradually diminished in numbers. Thus, iNKT subset diversification occurs in dividing progenitor cells without acute TCR input but utilizes multiple active cytokine signaling pathways. These data imply a two-step model of iNKT effector differentiation.

表达保守 TCR 的先天样 T 细胞群通过多种发育获得的效应子功能在免疫中发挥关键作用。专注于不变自然杀伤 T (iNKT) 细胞的原型谱系，我们试图剖析命运决定和功能效应器分化的机制和时间。利用双阳性胸腺细胞上半不变 NKT 细胞 TCR 的诱导表达，短暂的同质 TCR 信号触发了最初高度同步的 iNKT 细胞发育波。在达到以 IL-4 生产潜力和增殖为特征的统一祖细胞状态后，效应子亚群同时出现，但随后走向不同的命运。虽然 NKT17 规范很快完成，但 NKT1 细胞缓慢分化和扩增。NKT2 细胞类似于成熟的祖细胞，其数量逐渐减少。因此，iNKT 子集多样化发生在没有急性 TCR 输入但利用多种活性细胞因子信号通路的分裂祖细胞中。这些数据意味着 iNKT 效应器分化的两步模型。