The E-Id Protein Axis Specifies Adaptive Lymphoid Cell Identity and Suppresses Thymic Innate Lymphoid Cell Development

Immunity. 2017 May 16;46(5):818-834.e4. doi: 10.1016/j.immuni.2017.04.022.

Abstract

Innate and adaptive lymphoid development is orchestrated by the activities of E proteins and their antagonist Id proteins, but how these factors regulate early T cell progenitor (ETP) and innate lymphoid cell (ILC) development remains unclear. Using multiple genetic strategies, we demonstrated that E proteins E2A and HEB acted in synergy in the thymus to establish T cell identity and to suppress the aberrant development of ILCs, including ILC2s and lymphoid-tissue-inducer-like cells. E2A and HEB orchestrated T cell fate and suppressed the ILC transcription signature by activating the expression of genes associated with Notch receptors, T cell receptor (TCR) assembly, and TCR-mediated signaling. E2A and HEB acted in ETPs to establish and maintain a T-cell-lineage-specific enhancer repertoire, including regulatory elements associated with the Notch1, Rag1, and Rag2 loci. On the basis of these and previous observations, we propose that the E-Id protein axis specifies innate and adaptive lymphoid cell fate.

Keywords: E-ID protein axis; E2A; HEB; Notch signaling; T cell development; basic helix-loop-helix transcription factor; early T cell progenitor; innate lymphoid cell; regulome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity*
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cell Differentiation / immunology
  • Cluster Analysis
  • Gene Expression
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Gene Regulatory Networks
  • Immunity, Innate*
  • Immunomodulation*
  • Immunophenotyping
  • Inhibitor of Differentiation Protein 2 / genetics
  • Inhibitor of Differentiation Protein 2 / metabolism
  • Lymphocyte Activation / genetics
  • Lymphocyte Activation / immunology
  • Lymphocyte Subsets / cytology
  • Lymphocyte Subsets / immunology*
  • Lymphocyte Subsets / metabolism
  • Lymphoid Progenitor Cells / metabolism
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Phenotype
  • T-Cell Antigen Receptor Specificity / immunology
  • Thymocytes / cytology
  • Thymocytes / immunology*
  • Thymocytes / metabolism
  • Transcriptome

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Inhibitor of Differentiation Protein 2
  • Tcf3 protein, mouse