Journal Article

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

Nistala, Kiran, Evans, Jamie G., Mitchison, N. Avrion, Cambrook, Helen, Olivito, Biagio, Cimaz, Rolando, de Jager, Wilco, Adams, Stuart, Bajaj-Elliott, Mona, Wedderburn, Lucy R., Ursu, Simona

2010

Overview

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 TGFβ 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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Amino Acid Sequence / Animal models / Arthritis / Arthritis, Juvenile - genetics / Arthritis, Juvenile - immunology / Arthritis, Juvenile - metabolism / Base Sequence / Biological Sciences / CCR6 protein / CCR6 receptor / Cell Lineage - genetics / Cell Lineage - immunology / Child / Children / Children & youth / Cultured cells / Cytokines / double prime T-cell receptor / Flow Cytometry / Gene Expression / Genotype & phenotype / Helper cells / Humans / Inflammation / Inflammatory diseases / Interferon-gamma - genetics / Interferon-gamma - immunology / Interferon-gamma - metabolism / Interleukin 12 / Interleukin 17 / Interleukin 23 / Interleukin-12 - immunology / Interleukin-12 - metabolism / Interleukin-17 - genetics / Interleukin-17 - immunology / Interleukin-17 - metabolism / Joint diseases / Joints / Juvenile rheumatoid arthritis / Lymphocytes T / 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 / phenotype / Phenotypes / Plasticity / Receptors, CCR6 - genetics / Receptors, CCR6 - immunology / Receptors, CCR6 - metabolism / Reverse Transcriptase Polymerase Chain Reaction / Synovial fluid / T cell antigen receptors / T cell receptors / T lymphocytes / 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 / Transcription factors / Transforming Growth Factor beta - immunology / Transforming Growth Factor beta - metabolism / Transforming growth factor- beta