title: Th17 plasticity in human autoimmune arthritis is driven by the inflammatory environment.
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.
authors.affiliation: Rheumatology Unit, University College London Institute of Child Health, London WC1N 1EH, United Kingdom. K.Nistala@ich.ucl.ac.uk
authors.forename: Kiran
authors.initials: K
authors.lastname: Nistala
authors.forename: Stuart
authors.initials: S
authors.lastname: Adams
authors.forename: Helen
authors.initials: H
authors.lastname: Cambrook
authors.forename: Simona
authors.initials: S
authors.lastname: Ursu
authors.forename: Biagio
authors.initials: B
authors.lastname: Olivito
authors.forename: Wilco
authors.initials: W
authors.lastname: de Jager
authors.forename: Jamie G
authors.initials: JG
authors.lastname: Evans
authors.forename: Rolando
authors.initials: R
authors.lastname: Cimaz
authors.forename: Mona
authors.initials: M
authors.lastname: Bajaj-Elliott
authors.forename: Lucy R
authors.initials: LR
authors.lastname: Wedderburn
mesh_terms: D000595:Amino Acid Sequence; D001171:Arthritis, Juvenile / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D001483:Base Sequence; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D002648:Child; D005434:Flow Cytometry; D015870:Gene Expression; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008969:Molecular Sequence Data; D055651:NK Cell Lectin-Like Receptor Subfamily B / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D054399:Receptors, CCR6 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020825:T-Box Domain Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism; D000098815:T-bet Transcription Factor
chemical_list: C106311:CCR6 protein, human; D020381:Interleukin-17; C527203:KLRB1 protein, human; D055651:NK Cell Lectin-Like Receptor Subfamily B; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539900:RORC protein, human; D054399:Receptors, CCR6; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D016212:Transforming Growth Factor beta; D018664:Interleukin-12; D007371:Interferon-gamma