Musculin inhibits human T-helper 17 cell response to interleukin 2 by controlling STAT5B activity

Eur J Immunol. 2017 Sep;47(9):1427-1442. doi: 10.1002/eji.201746996. Epub 2017 Jul 6.

Abstract

We recently demonstrated that human T-helper (Th) 17 cells, unlike Th1 cells, do not proliferate in response to T-cell receptor stimulation, mainly because of their reduced capacity to produce and respond to IL-2. In this study, we show that their lower responsiveness to IL-2 is due to the selective expression of Musculin (MSC), a member of the basic helix-loop-helix transcription factors. We show that MSC expression in human Th17 cells is retinoic acid orphan receptor (ROR)γt-dependent, and allows the upregulation of PPP2R2B, a regulatory member of the protein phosphatase 2A (PP2A) enzyme. High PPP2R2B levels in human Th17 cells were responsible for the reduced STAT5B Ser-193 phosphorylation upon IL-2 signalling and, therefore, impaired STAT5B DNA binding and transcriptional activity on IL-2 target genes. PP2A, observed in Th17 cells, controls also STAT3, dephosphorylating Ser727, thus increasing its activity that plays a crucial role in Th17 development and/or maintenance. Thus, our findings identify an additional mechanism responsible for the limited expansion of human Th17 cells, and could provide a further explanation for the rarity of these cells in inflamed tissues.

Keywords: IL-2; Musculin; Proliferation; RORC; STAT5; Th17.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Cells, Cultured
  • Humans
  • Inflammation / immunology*
  • Interleukin-2 / immunology
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
  • Phosphorylation
  • Protein Binding
  • Protein Phosphatase 2 / genetics
  • Protein Phosphatase 2 / metabolism
  • STAT3 Transcription Factor / metabolism
  • STAT5 Transcription Factor / metabolism*
  • Th1 Cells / immunology*
  • Th17 Cells / immunology*
  • Up-Regulation

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Interleukin-2
  • MSC protein, human
  • Nerve Tissue Proteins
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • STAT5 Transcription Factor
  • STAT5B protein, human
  • PPP2CA protein, human
  • PPP2R2B protein, human
  • Protein Phosphatase 2