RORα is a critical checkpoint for T cell and ILC2 commitment in the embryonic thymus

Type 2 innate lymphoid cells (ILC2) contribute to immune homeostasis, protective immunity and tissue repair. Here we demonstrate that functional ILC2 can arise in the embryonic thymus, from shared T cell precursors, preceding the emergence of CD4(+)CD8(+) (double-positive) T cells. Thymic ILC2 migrated to mucosal tissues with colonization of the intestinal lamina propria. RORα expression repressed T cell development, while promoting ILC2 in the thymus. From RNA-seq, ATAC-seq and ChIP-seq data we propose a revised transcriptional circuit to explain the co-development of T cells and ILC2 from common progenitors in the thymus. When Notch signaling is present, Bcl11b dampens Nfil3/Id2 expression, permitting E protein-directed T cell commitment. However, concomitant expression of RORα overrides the Nfil3/Id2 repression, allowing Id2 to repress E proteins and promote ILC2 differentiation. Thus, we demonstrate that RORα expression represents a critical checkpoint at the bifurcation of the T cell and ILC2 lineages in the embryonic thymus.