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

Cell Rep. 2016 Feb 16;14(6):1500-1516. doi: 10.1016/j.celrep.2016.01.015. Epub 2016 Jan 28.

Abstract

T 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocyte Subsets / cytology
  • B-Lymphocyte Subsets / immunology*
  • Cell Differentiation
  • Cell Lineage / immunology
  • Cell Proliferation
  • Fetus
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental*
  • Immunity, Innate*
  • Inhibitor of Differentiation Protein 2 / genetics
  • Inhibitor of Differentiation Protein 2 / immunology
  • Integrins / genetics
  • Integrins / immunology
  • Mice
  • Mice, Transgenic
  • Receptors, Notch / genetics
  • Receptors, Notch / immunology
  • Signal Transduction*
  • Single-Cell Analysis
  • Stem Cells / cytology
  • Stem Cells / immunology
  • T-Lymphocyte Subsets / cytology
  • T-Lymphocyte Subsets / immunology*
  • Transcription, Genetic
  • Transcriptome
  • fms-Like Tyrosine Kinase 3 / genetics
  • fms-Like Tyrosine Kinase 3 / immunology

Substances

  • Idb2 protein, mouse
  • Inhibitor of Differentiation Protein 2
  • Integrins
  • Receptors, Notch
  • integrin alpha4beta7
  • Flt3 protein, mouse
  • fms-Like Tyrosine Kinase 3