Synergy between IL-15 and Id2 promotes the expansion of human NK progenitor cells, which can be counteracted by the E protein HEB required to drive T cell development

J Immunol. 2010 Jun 15;184(12):6670-9. doi: 10.4049/jimmunol.0901508. Epub 2010 May 10.

Abstract

The cytokine IL-15 and the inhibitor of DNA binding (Id)2, which negatively regulates the activity of basic helix-loop-helix transcription factors, have been shown to play key roles in NK cell development. Consistent with this, exogenous IL-15 added to human thymic progenitor cells stimulated their development into NK cells at the expense of T cells both in fetal thymic organ culture and in coculture with stromal cells expressing the Notch ligand Delta-like 1. Overexpression of Id2 in thymic progenitor cells stimulated NK cell development and blocked T cell development. This, in part, is attributed to inhibition of the transcriptional activity of the E protein HEB, which we show in this study is the only E protein that enhanced T cell development. Notably, Id2 increased a pool of lineage CD1a-CD5+ progenitor cells that in synergy with IL-15 furthered expansion and differentiation into NK cells. Taken together, our findings point to a dualistic function of Id2 in controlling T/NK cell lineage decisions; T cell development is impaired by Id2, most likely by sequestering HEB, whereas NK cell development is promoted by increasing a pool of CD1a-CD5+ NK cell progenitors, which together with IL-15 differentiate into mature NK cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Basic Helix-Loop-Helix Transcription Factors / immunology*
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cell Differentiation / immunology*
  • Cell Lineage / immunology
  • Cell Separation
  • Flow Cytometry
  • Hematopoietic Stem Cells / immunology*
  • Hematopoietic Stem Cells / metabolism
  • Humans
  • Inhibitor of Differentiation Protein 2 / immunology*
  • Inhibitor of Differentiation Protein 2 / metabolism
  • Interleukin-15 / immunology*
  • Interleukin-15 / metabolism
  • Killer Cells, Natural / cytology
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • ID2 protein, human
  • Inhibitor of Differentiation Protein 2
  • Interleukin-15
  • TCF12 protein, human