The development of innate lymphoid cells requires TOX-dependent generation of a common innate lymphoid cell progenitor

Nat Immunol. 2015 Jun;16(6):599-608. doi: 10.1038/ni.3168. Epub 2015 Apr 27.


Diverse innate lymphoid cell (ILC) subtypes have been defined on the basis of effector function and transcription factor expression. ILCs derive from common lymphoid progenitors, although the transcriptional pathways that lead to ILC-lineage specification remain poorly characterized. Here we found that the transcriptional regulator TOX was required for the in vivo differentiation of common lymphoid progenitors into ILC lineage-restricted cells. In vitro modeling demonstrated that TOX deficiency resulted in early defects in the survival or proliferation of progenitor cells, as well as ILC differentiation at a later stage. In addition, comparative transcriptome analysis of bone marrow progenitors revealed that TOX-deficient cells failed to upregulate many genes of the ILC program, including genes that are targets of Notch, which indicated that TOX is a key determinant of early specification to the ILC lineage.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bone Marrow Cells / physiology
  • Cell Differentiation / genetics
  • Cell Lineage / genetics
  • Cell Proliferation / genetics
  • Cell Survival / genetics
  • Cells, Cultured
  • Female
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Immunity, Innate / genetics
  • Killer Cells, Natural / physiology*
  • Lymphocyte Subsets / physiology*
  • Lymphoid Progenitor Cells / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Receptors, Notch / genetics
  • Receptors, Notch / metabolism*
  • Transcriptome


  • Homeodomain Proteins
  • Receptors, Notch
  • Rhox8 protein, mouse

Associated data

  • GEO/GSE65850