1. RORa is a critical checkpoint for T cell and ILC2 commitment in the embryonic thymus
- Author
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Ferreira, Ana C. F., Szeto, Aydan C. H., Heycock, Morgan W. D., Clark, Paula A., Walker, Jennifer A., Crisp, Alastair, Barlow, Jillian L., Kitching, Sophie, Lim, Alfred, Gogoi, Mayuri, Berks, Richard, Daly, Maria, Jolin, Helen E., and McKenzie, Andrew N. J.
- Abstract
Type 2 innate lymphoid cells (ILC2) contribute to immune homeostasis, protective immunity and tissue repair. Here we demonstrate that functional ILC2 cells can arise in the embryonic thymus from shared T cell precursors, preceding the emergence of CD4+CD8+(double-positive) T cells. Thymic ILC2 cells migrated to mucosal tissues, with colonization of the intestinal lamina propria. Expression of the transcription factor RORa repressed T cell development while promoting ILC2 development in the thymus. From RNA-seq, assay for transposase-accessible chromatin sequencing (ATAC-seq) and chromatin immunoprecipitation followed by sequencing (ChIP-seq) data, we propose a revised transcriptional circuit to explain the co-development of T cells and ILC2 cells from common progenitors in the thymus. When Notch signaling is present, BCL11B dampens Nfil3and Id2expression, permitting E protein–directed T cell commitment. However, concomitant expression of RORa overrides the repression of Nfil3and Id2repression, allowing ID2 to repress E proteins and promote ILC2 differentiation. Thus, we demonstrate that RORa expression represents a critical checkpoint at the bifurcation of the T cell and ILC2 lineages in the embryonic thymus.
- Published
- 2021
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