The cytokines IL-21 and GM-CSF have opposing regulatory roles in the apoptosis of conventional dendritic cells

Immunity. 2013 Mar 21;38(3):514-27. doi: 10.1016/j.immuni.2013.02.011. Epub 2013 Feb 28.

Abstract

Interleukin-21 (IL-21) has broad actions on T and B cells, but its actions in innate immunity are poorly understood. Here we show that IL-21 induced apoptosis of conventional dendritic cells (cDCs) via STAT3 and Bim, and this was inhibited by granulocyte-macrophage colony-stimulating factor (GM-CSF). ChIP-Seq analysis revealed genome-wide binding competition between GM-CSF-induced STAT5 and IL-21-induced STAT3. Expression of IL-21 in vivo decreased cDC numbers, and this was prevented by GM-CSF. Moreover, repetitive α-galactosylceramide injection of mice induced IL-21 but decreased GM-CSF production by natural killer T (NKT) cells, correlating with decreased cDC numbers. Furthermore, adoptive transfer of wild-type CD4+ T cells caused more severe colitis with increased DCs and interferon-γ (IFN-γ)-producing CD4+ T cells in Il21r(-/-)Rag2(-/-) mice (which lack T cells and have IL-21-unresponsive DCs) than in Rag2(-/-) mice. Thus, IL-21 and GM-CSF exhibit cross-regulatory actions on gene regulation and apoptosis, regulating cDC numbers and thereby the magnitude of the immune response.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / immunology*
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / immunology
  • Apoptosis Regulatory Proteins / metabolism
  • Bcl-2-Like Protein 11
  • Blotting, Western
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • Cells, Cultured
  • DNA, Intergenic / genetics
  • DNA, Intergenic / immunology
  • DNA, Intergenic / metabolism
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / immunology
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Flow Cytometry
  • Galactosylceramides / immunology
  • Galactosylceramides / pharmacology
  • Gene Expression / drug effects
  • Gene Expression / immunology
  • Granulocyte-Macrophage Colony-Stimulating Factor / genetics
  • Granulocyte-Macrophage Colony-Stimulating Factor / immunology*
  • Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism
  • Interleukins / genetics
  • Interleukins / immunology*
  • Interleukins / pharmacology
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Natural Killer T-Cells / drug effects
  • Natural Killer T-Cells / immunology
  • Natural Killer T-Cells / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Protein Binding / immunology
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / immunology
  • Proto-Oncogene Proteins / metabolism
  • Receptors, Interleukin-21 / deficiency
  • Receptors, Interleukin-21 / genetics
  • Receptors, Interleukin-21 / immunology
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / immunology
  • STAT3 Transcription Factor / metabolism
  • STAT5 Transcription Factor / genetics
  • STAT5 Transcription Factor / immunology
  • STAT5 Transcription Factor / metabolism

Substances

  • Apoptosis Regulatory Proteins
  • Bcl-2-Like Protein 11
  • Bcl2l11 protein, mouse
  • DNA, Intergenic
  • DNA-Binding Proteins
  • Galactosylceramides
  • Interleukins
  • Membrane Proteins
  • Proto-Oncogene Proteins
  • Rag2 protein, mouse
  • Receptors, Interleukin-21
  • STAT3 Transcription Factor
  • STAT5 Transcription Factor
  • Stat3 protein, mouse
  • alpha-galactosylceramide
  • Interferon-gamma
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • interleukin-21

Associated data

  • GEO/GSE27161