Autoimmune arthritis in childhood, know as juvenile idiopathic arthritis (JIA), has a
heterogeneity, ranging from monoarthritis to recalcitrant polyarthritis, making it a model
disease in which to study immuno-regulation. Regulatory T cells, key players in
peripheral immune homeostasis are enriched in the joints of JIA patients, particularly
those with mild arthritis. To test the factors that lead to this enrichment, Treg trafficking
was examined in the context of JIA. Synovial Treg showed enhanced chemotaxis to the
inflammatory chemokine CCL5, widely detectable within the joint, when compared to
Treg from peripheral blood. The trafficking of a related, but highly inflammatory T cell
subset, Th17 cells, was also investigated. Th17 cells play a dominant role in murine
models of arthritis, yet their contribution to human disease is unknown. The data
presented here, showed that IL-17+ CD4 T cells were enriched in the joints of JIA
patients, by a CCR6 dependent mechanism and importantly, their frequency correlated
with the severity of disease course.
The majority of synovial IL-17+ CD4 T cells expressed a cytokine and chemokine
receptor phenotype intermediate between Th17 and Th1. Here it was shown that these
cells (Th17/1) expressed high levels of both Th17 and Th1 specific transcription factors,
RORC2 and T-bet. Modelling the generation of Th17/1 in vitro, Th17 cells ‘converted’
to Th17/1 under conditions which mimicked the disease site, namely low TGFβ and high
IL-12 levels. Using CD161, a human Th17 marker, it was shown that synovial Th17/1
cells, and unexpectedly, a large proportion of Th1 cells expressed CD161. This study
provided evidence to support a Th17 origin for Th1 cells expressing CD161. In vitro,
Th17 cells which converted to a Th1 phenotype maintained CD161 expression, whilst in
the joint CD161+ Th1 cells shared features with Th17 cells, with shared T cell receptor
clonality and expression of RORC2, although they were IL-17 negative. We propose 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 the Th17/1 and Th1 effector
populations within the inflamed joint