TNF-α blockade induces IL-10 expression in human CD4+ T cells

Nat Commun. 2014;5:3199. doi: 10.1038/ncomms4199.

Abstract

IL-17+ CD4+ T (Th17) cells contribute to the pathogenesis of several human inflammatory diseases. Here we demonstrate that TNF inhibitor (TNFi) drugs induce the anti-inflammatory cytokine IL-10 in CD4+ T cells including IL-17+ CD4+ T cells. TNFi-mediated induction of IL-10 in IL-17+ CD4+ T cells is Treg-/Foxp3-independent, requires IL-10 and is overcome by IL-1β. TNFi-exposed IL-17+ CD4+ T cells are molecularly and functionally distinct, with a unique gene signature characterized by expression of IL10 and IKZF3 (encoding Aiolos). We show that Aiolos binds conserved regions in the IL10 locus in IL-17+ CD4+ T cells. Furthermore, IKZF3 and IL10 expression levels correlate in primary CD4+ T cells and Aiolos overexpression is sufficient to drive IL10 in these cells. Our data demonstrate that TNF-α blockade induces IL-10 in CD4+ T cells including Th17 cells and suggest a role for the transcription factor Aiolos in the regulation of IL-10 in CD4+ T cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antirheumatic Agents / pharmacology*
  • Antirheumatic Agents / therapeutic use
  • Arthritis, Rheumatoid / drug therapy*
  • Arthritis, Rheumatoid / immunology
  • Base Sequence
  • Case-Control Studies
  • Cattle
  • Cells, Cultured
  • Conserved Sequence
  • Dogs
  • Humans
  • Ikaros Transcription Factor / metabolism
  • Interleukin-10 / metabolism*
  • Interleukin-1beta / metabolism
  • Mice
  • Molecular Sequence Data
  • Rats
  • Sequence Homology, Nucleic Acid
  • Th17 Cells / drug effects*
  • Th17 Cells / metabolism
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*

Substances

  • Antirheumatic Agents
  • IKZF3 protein, human
  • IL10 protein, human
  • Interleukin-1beta
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • Ikaros Transcription Factor