Podoplanin is a negative regulator of Th17 inflammation

JCI Insight. 2017 Sep 7;2(17):e92321. doi: 10.1172/jci.insight.92321.

Abstract

Recent data indicate that there are different subpopulations of Th17 cells that can express a regulatory as opposed to an inflammatory gene signature. The transmembrane glycoprotein PDPN is critical in the development of multiple organs including the lymphatic system and has been described on T cells in mouse models of autoimmune Th17 inflammation. Here, we demonstrate that unlike in mice, PDPN+ T cells induced under classic Th17-polarizing conditions express transcription factors associated with Th17 cells but do not produce IL-17. Moreover, these cells express a transcriptional profile enriched for immunosuppressive and regulatory pathways and express a distinct cytokine profile compared with potentially pathogenic PDPN- Th17 cells. Ligation of PDPN by its ligand CLEC-2 ameliorates the Th17 inflammatory response. IL-17 secretion is restored with shRNA gene silencing of PDPN. Furthermore, PDPN expression is reduced via an Sgk1-mediated pathway under proinflammatory, high sodium chloride conditions. Finally, CD3+PDPN+ T cells are devoid of IL-17 in skin biopsies from patients with candidiasis, a prototypical Th17-driven skin disease. Thus, our data support the hypothesis that PDPN may serve as a marker of a nonpathogenic Th17 cell subset and may also functionally regulate pathogenic Th17 inflammation.

Keywords: Autoimmunity; Cytokines; Fungal infections; Immunology; T cells.

Publication types

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

MeSH terms

  • Cells, Cultured
  • Cytokines / metabolism
  • Gene Expression Profiling
  • Gene Silencing
  • Humans
  • Immediate-Early Proteins / metabolism
  • Inflammation / pathology*
  • Interleukin-17 / biosynthesis
  • Lectins, C-Type / metabolism
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Membrane Glycoproteins / physiology*
  • Protein Serine-Threonine Kinases / metabolism
  • RNA, Small Interfering / genetics
  • Th17 Cells / metabolism
  • Th17 Cells / pathology*
  • Transcription, Genetic

Substances

  • CLEC2B protein, human
  • Cytokines
  • Immediate-Early Proteins
  • Interleukin-17
  • Lectins, C-Type
  • Membrane Glycoproteins
  • PDPN protein, human
  • RNA, Small Interfering
  • Protein Serine-Threonine Kinases
  • serum-glucocorticoid regulated kinase