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 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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Basic-Leucine Zipper Transcription Factors / genetics
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Basic-Leucine Zipper Transcription Factors / metabolism
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism*
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / metabolism*
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Cell Differentiation*
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Cell Lineage*
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Cell Movement
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Cells, Cultured
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Coculture Techniques
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Female
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Gene Expression Regulation, Developmental
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Immunity, Innate*
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Inhibitor of Differentiation Protein 2 / genetics
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Inhibitor of Differentiation Protein 2 / metabolism
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Nuclear Receptor Subfamily 1, Group F, Member 1 / genetics
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Nuclear Receptor Subfamily 1, Group F, Member 1 / metabolism*
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Organ Culture Techniques
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Phenotype
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Signal Transduction
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Thymocytes / immunology
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Thymocytes / metabolism*
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Thymus Gland / embryology
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Thymus Gland / immunology
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Thymus Gland / metabolism*
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
Substances
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Basic-Leucine Zipper Transcription Factors
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Bcl11b protein, mouse
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Idb2 protein, mouse
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Inhibitor of Differentiation Protein 2
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Nfil3 protein, mouse
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Nuclear Receptor Subfamily 1, Group F, Member 1
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Repressor Proteins
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Rora protein, mouse
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Tumor Suppressor Proteins