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

Area of Science:

• Immunology
• Developmental Biology

Background:

• Type 2 innate lymphoid cells (ILC2) are crucial for immune homeostasis, tissue repair, and protective immunity.
• The developmental origins and early differentiation pathways of ILC2s remain incompletely understood.

Purpose of the Study:

• To investigate the potential for ILC2 development within the embryonic thymus.
• To elucidate the molecular mechanisms governing the co-development of T cells and ILC2s from common progenitors.

Main Methods:

• RNA-sequencing (RNA-seq)
• Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq)
• Chromatin Immunoprecipitation followed by sequencing (ChIP-seq)
• Analysis of transcription factor expression (RORα, BCL11B, Nfil3, Id2) and signaling pathways (Notch).

Main Results:

• Functional ILC2 cells arise in the embryonic thymus from shared T cell precursors, preceding CD4+CD8+ T cell emergence.
• Thymic ILC2s migrate to and colonize mucosal tissues, including the intestinal lamina propria.
• RORα expression represses T cell development while promoting ILC2 development.
• A revised transcriptional circuit involving RORα, BCL11B, Nfil3, Id2, and E proteins explains the lineage bifurcation.

Conclusions:

• RORα acts as a critical checkpoint regulating the divergence of T cell and ILC2 lineages in the embryonic thymus.
• This study reveals a novel developmental pathway for ILC2s originating in the thymus.