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

• Published in: Nature immunology Vol. 22; no. 2; pp. 166 - 178
• Main Authors: 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., McKenzie, Andrew N. J.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2021; Nature Publishing Group
• Subjects: 631/250; 631/250/1619; 631/250/2504/2506; Animals; Basic-Leucine Zipper Transcription Factors - genetics; Basic-Leucine Zipper Transcription Factors - metabolism; Biomedical and Life Sciences; Biomedicine; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Differentiation; Cell Lineage; Cell Movement; Cells, Cultured; Chromatin; Coculture Techniques; Colonization; E protein; Embryos; Female; Gene Expression Regulation, Developmental; Homeostasis; Immunity, Innate; Immunology; Immunoprecipitation; Infectious Diseases; Inhibitor of Differentiation Protein 2 - genetics; Inhibitor of Differentiation Protein 2 - metabolism; Intestine; Lamina propria; Lymphocytes; Lymphocytes T; Lymphoid cells; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mucosa; Nuclear Receptor Subfamily 1, Group F, Member 1 - genetics; Nuclear Receptor Subfamily 1, Group F, Member 1 - metabolism; Organ Culture Techniques; Phenotype; Repressor Proteins - genetics; Repressor Proteins - metabolism; Ribonucleic acid; RNA; Signal Transduction; Stem cells; Thymocytes - immunology; Thymocytes - metabolism; Thymus; Thymus gland; Thymus Gland - embryology; Thymus Gland - immunology; Thymus Gland - metabolism; Transposase; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/s41590-020-00833-w

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 RORα 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 Nfil3 and Id2 expression, permitting E protein–directed T cell commitment. However, concomitant expression of RORα overrides the repression of Nfil3 and 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. McKenzie and colleagues show RORα expression in early thymic progenitors overrides BCL11B-dependent suppression of Id2 and Nfil3 expression. In turn, ID2 suppresses the activity of the E proteins that are required for T lineage development, thereby promoting ILC2 cell generation in the thymus.