Multipotent hematopoietic progenitors must acquire thymus-homing capacity to initiate T lymphocyte development. Despite its importance, the transcriptional program underlying this process remains elusive. Cbfβ forms transcription factor complexes with Runx proteins, and here we show that Cbfβ2, encoded by an RNA splice variant of the Cbfb gene, is essential for extrathymic differentiation of T cell progenitors. Furthermore, Cbfβ2 endows extrathymic progenitors with thymus-homing capacity by inducing expression of the principal thymus-homing receptor, Ccr9. This occurs via direct binding of Cbfβ2 to cell type–specific enhancers, as is observed in Rorγt induction during differentiation of lymphoid tissue inducer cells by activation of an intronic enhancer. As in mice, an alternative splicing event in zebrafish generates a Cbfβ2-specific mRNA, important for ccr9 expression. Thus, despite phylogenetically and ontogenetically variable sites of origin of T cell progenitors, their robust thymus-homing capacity is ensured by an evolutionarily conserved mechanism emerging from functional diversification of Runx transcription factor complexes by acquisition of a novel splice variant.

多能造血祖细胞必须获得胸腺归巢能力才能启动T淋巴细胞的发育。尽管它很重要，但该过程的转录程序仍然难以捉摸。CBFβ形成转录因子复合物与RUNX蛋白，在这里，我们表明Cbfβ2，由一个RNA剪接变体编码CBFB该基因对于T细胞祖细胞的胸腺外分化至关重要。此外，Cbfβ2通过诱导主要胸腺归巢受体Ccr9的表达赋予胸腺外祖细胞以胸腺归巢的能力。这是通过Cbfβ2与细胞类型特异性增强子的直接结合而发生的，正如在通过内含性增强子激活而使淋巴组织诱导细胞分化过程中在Rorγt诱导中观察到的那样。与小鼠一样，斑马鱼中的另一种剪接事件会产生Cbfβ2特异性mRNA，对ccr9很重要表达。因此，尽管存在T细胞祖细胞的系统发育和个体发育可变位点，但通过获得新的剪接变体从Runx转录因子复合物的功能多样化发展而来的进化保守机制确保了其鲁棒的胸腺归巢能力。