Suppression of ILC2 differentiation from committed T cell precursors by E protein transcription factors

J Exp Med. 2019 Apr 1;216(4):884-899. doi: 10.1084/jem.20182100. Epub 2019 Mar 21.

Abstract

Current models propose that group 2 innate lymphoid cells (ILC2s) are generated in the bone marrow. Here, we demonstrate that subsets of these cells can differentiate from multipotent progenitors and committed T cell precursors in the thymus, both in vivo and in vitro. These thymic ILC2s exit the thymus, circulate in the blood, and home to peripheral tissues. Ablation of E protein transcription factors greatly promotes the ILC fate while impairing B and T cell development. Consistently, a transcriptional network centered on the ZBTB16 transcription factor and IL-4 signaling pathway is highly up-regulated due to E protein deficiency. Our results show that ILC2 can still arise from what are normally considered to be committed T cell precursors, and that this alternative cell fate is restrained by high levels of E protein activity in these cells. Thymus-derived lung ILC2s of E protein-deficient mice show different transcriptomes, proliferative properties, and cytokine responses from wild-type counterparts, suggesting potentially distinct functions.

Publication types

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

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Cell Differentiation / physiology*
  • Cell Line
  • Interleukin-4 / metabolism
  • Lung / cytology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Nude
  • Precursor Cells, T-Lymphoid / metabolism*
  • Promyelocytic Leukemia Zinc Finger Protein / metabolism
  • Thymus Gland / cytology
  • Transcription Factor 4 / genetics
  • Transcription Factor 4 / metabolism*
  • Transcription, Genetic
  • Transcriptome

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Il4 protein, mouse
  • Promyelocytic Leukemia Zinc Finger Protein
  • Tcf12 protein, mouse
  • Tcf3 protein, mouse
  • Tcf4 protein, mouse
  • Transcription Factor 4
  • Zbtb16 protein, mouse
  • Interleukin-4