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