Single-Cell Gene Expression Analyses Reveal Heterogeneous Responsiveness of Fetal Innate Lymphoid Progenitors to Notch Signaling

• Global ILC progenitor and T precursors are found in the αLP1 compartment
• αLP2 compartment is heterogeneously composed of primed ILC precursors
• Notch signaling specifically acts on proliferation of an αLP2 ILC2 primed subset
• Constitutive NICD expression drives T cell development and restrains Id2 expression

SummaryT and innate lymphoid cells (ILCs) share some aspects of their developmental programs. However, although Notch signaling is strictly required for T cell development, it is dispensable for fetal ILC development. Constitutive activation of Notch signaling, at the common lymphoid progenitor stage, drives T cell development and abrogates ILC development by preventing Id2 expression. By combining single-cell transcriptomics and clonal culture strategies, we characterize two heterogeneous α4β7-expressing lymphoid progenitor compartments. αLP1 (Flt3+) still retains T cell potential and comprises the global ILC progenitor, while αLP2 (Flt3−) consists of ILC precursors that are primed toward the different ILC lineages. Only a subset of αLP2 precursors is sensitive to Notch signaling required for their proliferation. Our study identifies, in a refined manner, the diversity of transitional stages of ILC development, their transcriptional signatures, and their differential dependence on Notch signaling.

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