Death receptor 3 signaling enhances proliferation of human regulatory T cells

FEBS Lett. 2017 Apr;591(8):1187-1195. doi: 10.1002/1873-3468.12632. Epub 2017 Apr 10.

Abstract

Exploiting regulatory T cells (Tregs) to control aberrant immune reactions is a promising therapeutic approach, but is hampered by their relative paucity. In mice, activation of death receptor 3 (DR3), a member of the TNF-receptor superfamily (TNFRSF), increases Treg frequency and efficiently controls exuberant immune activation. For human Tregs, neither DR3 expression nor potential functions have been described. Here, we show that human Tregs express DR3 and demonstrate DR3-mediated activation of p38, ERK, and NFκB. DR3 stimulation enhances Treg expansion ex vivo while retaining their suppressive capacity. In summary, our results establish a functional role for DR3 signaling in human Tregs and could potentially help to tailor Treg-based therapies.

Keywords: DR3; TL1A; TNFRSF25; TNFSF15; Treg.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Humans
  • Immunosuppressive Agents / pharmacology
  • Ligands
  • MAP Kinase Signaling System* / drug effects
  • NF-kappa B p52 Subunit / agonists*
  • NF-kappa B p52 Subunit / metabolism
  • Peptide Fragments / chemistry
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism
  • Phosphorylation / drug effects
  • Protein Interaction Domains and Motifs
  • Protein Isoforms / chemistry
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Processing, Post-Translational / drug effects
  • Receptors, Tumor Necrosis Factor, Member 25 / agonists*
  • Receptors, Tumor Necrosis Factor, Member 25 / chemistry
  • Receptors, Tumor Necrosis Factor, Member 25 / genetics
  • Receptors, Tumor Necrosis Factor, Member 25 / metabolism
  • Receptors, Tumor Necrosis Factor, Type II / chemistry
  • Receptors, Tumor Necrosis Factor, Type II / genetics
  • Receptors, Tumor Necrosis Factor, Type II / metabolism
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction* / drug effects
  • Sirolimus / pharmacology
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism*
  • Tumor Necrosis Factor Ligand Superfamily Member 15 / chemistry
  • Tumor Necrosis Factor Ligand Superfamily Member 15 / genetics
  • Tumor Necrosis Factor Ligand Superfamily Member 15 / metabolism*
  • Up-Regulation* / drug effects

Substances

  • Immunosuppressive Agents
  • Ligands
  • NF-kappa B p52 Subunit
  • NFKB2 protein, human
  • Peptide Fragments
  • Protein Isoforms
  • Receptors, Tumor Necrosis Factor, Member 25
  • Receptors, Tumor Necrosis Factor, Type II
  • Recombinant Fusion Proteins
  • TNFRSF1B protein, human
  • TNFRSF25 protein, human
  • TNFSF15 protein, human
  • Tumor Necrosis Factor Ligand Superfamily Member 15
  • Sirolimus