Irf4 Regulates the Choice between T Lymphoid-Primed Progenitor and Myeloid Lineage Fates during Embryogenesis

T lymphoid-primed progenitors are hematopoietic progenitors destined to enter the thymus. The in vivo characterization of these embryonic progenitors is challenging, however, due to the intrauterine development of mouse embryos. Thus, how the fate of these cells is determined has not been fully defined in mammals. Here we use zebrafish embryos to show that the homing of T lymphoid-primed progenitors to the thymus is impaired, concomitant with a decrease in ccr9a expression, in the absence of irf4a. Strikingly, fate mapping assays at the single-cell level showed a fate change of irf4a-deficient T lymphoid-primed progenitors to myeloid cells, accompanied by an increase in Pu.1 expression. These data indicate that in addition to regulating ccr9a expression, Irf4a is essential in T lymphoid-primed progenitors for repressing Pu.1 expression to prevent an alternate fate. Our findings provide insight into the fate determination mechanism of T lymphoid-primed progenitors. [Display omitted] •At the prethymic stage, Irf4 is critical for the T lymphoid-primed progenitor fate•Irf4a regulates ccr9a in T lymphoid-primed progenitors homing to the thymus•Irf4a prevents conversion of these progenitors to myeloid cells by repressing Pu.1 T cell development during the prethymic stage, which occurs during embryogenesis, has been difficult to study in vivo. Here, Wang et al. use zebrafish to study early T cell lineage commitment and find that the Irf4a transcription factor is required to prevent T lymphoid-primed progenitors from adopting the myeloid fate.