Trans-presentation of IL-6 by dendritic cells is required for the priming of pathogenic T H 17 cells

Nat Immunol. 2017 Jan;18(1):74-85. doi: 10.1038/ni.3632. Epub 2016 Nov 28.

Abstract

The cellular sources of interleukin 6 (IL-6) that are relevant for differentiation of the TH17 subset of helper T cells remain unclear. Here we used a novel strategy for the conditional deletion of distinct IL-6-producing cell types to show that dendritic cells (DCs) positive for the signaling regulator Sirpα were essential for the generation of pathogenic TH17 cells. Using their IL-6 receptor α-chain (IL-6Rα), Sirpα+ DCs trans-presented IL-6 to T cells during the process of cognate interaction. While ambient IL-6 was sufficient to suppress the induction of expression of the transcription factor Foxp3 in T cells, trans-presentation of IL-6 by DC-bound IL-6Rα (called 'IL-6 cluster signaling' here) was needed to prevent premature induction of interferon-γ (IFN-γ) expression in T cells and to generate pathogenic TH17 cells in vivo. Our findings should guide therapeutic approaches for the treatment of TH17-cell-mediated autoimmune diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoimmunity
  • Cell Differentiation
  • Cells, Cultured
  • Central Nervous System / immunology*
  • Dendritic Cells / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Humans
  • Interleukin-6 / metabolism*
  • Interleukin-6 Receptor alpha Subunit / genetics*
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myelin-Oligodendrocyte Glycoprotein / immunology
  • Peptide Fragments / immunology
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism
  • Th17 Cells / immunology*

Substances

  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Interleukin-6
  • Interleukin-6 Receptor alpha Subunit
  • Myelin-Oligodendrocyte Glycoprotein
  • Peptide Fragments
  • Ptpns1 protein, mouse
  • Receptors, Immunologic
  • myelin oligodendrocyte glycoprotein (35-55)