Th17 plasticity in human autoimmune arthritis is driven by the inflammatory environment

Proc Natl Acad Sci U S A. 2010 Aug 17;107(33):14751-6. doi: 10.1073/pnas.1003852107. Epub 2010 Aug 2.

Abstract

In several murine models of autoimmune arthritis, Th17 cells are the dominant initiators of inflammation. In human arthritis the majority of IL-17-secreting cells within the joint express a cytokine phenotype intermediate between Th17 and Th1. Here we show that Th17/1 cells from the joints of children with inflammatory arthritis express high levels of both Th17 and Th1 lineage-specific transcription factors, RORC2 and T-bet. Modeling the generation of Th17/1 in vitro, we show that Th17 cells "convert" to Th17/1 under conditions that mimic the disease site, namely low TGFbeta and high IL-12 levels, whereas Th1 cells cannot convert to Th17. Th17/1 cells from the inflamed joint share T-cell receptor (TCR) clonality with Th17 cells, suggesting a shared clonal origin between Th17 and Th17/1 cells in arthritis. Using CD161, a lectin-like receptor that is a marker of human Th17, we show synovial Th17 and Th17/1 cells, and unexpectedly, a large proportion of Th1 cells express CD161. We provide evidence to support a Th17 origin for Th1 cells expressing CD161. In vitro, Th17 cells that convert to a Th1 phenotype maintain CD161 expression. In the joint CD161+ Th1 cells share features with Th17 cells, with shared TCR clonality, expression of RORC2 and CCR6 and response to IL-23, although they are IL-17 negative. We propose that the Th17 phenotype may be unstable and that Th17 cells may convert to Th17/1 and Th1 cells in human arthritis. Therefore therapies targeting the induction of Th17 cells could also attenuate Th17/1 and Th1 effector populations within the inflamed joint.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Arthritis, Juvenile / genetics
  • Arthritis, Juvenile / immunology*
  • Arthritis, Juvenile / metabolism
  • Base Sequence
  • Cell Lineage / genetics
  • Cell Lineage / immunology
  • Child
  • Flow Cytometry
  • Gene Expression
  • Humans
  • Interferon-gamma / genetics
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism
  • Interleukin-12 / immunology
  • Interleukin-12 / metabolism
  • Interleukin-17 / genetics
  • Interleukin-17 / immunology*
  • Interleukin-17 / metabolism
  • Molecular Sequence Data
  • NK Cell Lectin-Like Receptor Subfamily B / genetics
  • NK Cell Lectin-Like Receptor Subfamily B / immunology
  • NK Cell Lectin-Like Receptor Subfamily B / metabolism
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / immunology
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
  • Receptors, CCR6 / genetics
  • Receptors, CCR6 / immunology
  • Receptors, CCR6 / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • T-Box Domain Proteins / genetics
  • T-Box Domain Proteins / immunology
  • T-Box Domain Proteins / metabolism
  • T-Lymphocytes, Helper-Inducer / immunology*
  • T-Lymphocytes, Helper-Inducer / metabolism
  • Th1 Cells / immunology*
  • Th1 Cells / metabolism
  • Transforming Growth Factor beta / immunology
  • Transforming Growth Factor beta / metabolism

Substances

  • CCR6 protein, human
  • Interleukin-17
  • KLRB1 protein, human
  • NK Cell Lectin-Like Receptor Subfamily B
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • RORC protein, human
  • Receptors, CCR6
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • Transforming Growth Factor beta
  • Interleukin-12
  • Interferon-gamma