Subsets of ILC3-ILC1-like cells generate a diversity spectrum of innate lymphoid cells in human mucosal tissues

Nat Immunol. 2019 Aug;20(8):980-991. doi: 10.1038/s41590-019-0425-y. Epub 2019 Jun 17.

Abstract

Innate lymphoid cells (ILCs) are tissue-resident lymphocytes categorized on the basis of their core regulatory programs and the expression of signature cytokines. Human ILC3s that produce the cytokine interleukin-22 convert into ILC1-like cells that produce interferon-γ in vitro, but whether this conversion occurs in vivo remains unclear. In the present study we found that ILC3s and ILC1s in human tonsils represented the ends of a spectrum that included additional discrete subsets. RNA velocity analysis identified an intermediate ILC3-ILC1 cluster, which had strong directionality toward ILC1s. In humanized mice, the acquisition of ILC1 features by ILC3s showed tissue dependency. Chromatin studies indicated that the transcription factors Aiolos and T-bet cooperated to repress regulatory elements active in ILC3s. A transitional ILC3-ILC1 population was also detected in the human intestine. We conclude that ILC3s undergo conversion into ILC1-like cells in human tissues in vivo, and that tissue factors and Aiolos were required for this process.

Publication types

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

MeSH terms

  • Animals
  • Cell Differentiation / immunology
  • Cells, Cultured
  • Child
  • Child, Preschool
  • Humans
  • Ikaros Transcription Factor / metabolism
  • Immunity, Innate / immunology*
  • Interferon-gamma / metabolism*
  • Interleukins / metabolism*
  • Intestinal Mucosa / cytology
  • Intestinal Mucosa / immunology*
  • Lymphocytes / classification
  • Lymphocytes / cytology
  • Lymphocytes / immunology*
  • Mice
  • Palatine Tonsil / immunology*
  • T-Box Domain Proteins / metabolism

Substances

  • IFNG protein, human
  • IKZF3 protein, human
  • Interleukins
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • Ikaros Transcription Factor
  • Interferon-gamma
  • interleukin-22