Cellular Interactions of Synovial Fluid γδ T Cells in Juvenile Idiopathic Arthritis

The pathogenesis of juvenile idiopathic arthritis (JIA) is thought to involve multiple components of the cellular immune system, including subsets of gamma delta T cells. In this study, we conducted experiments to define the functional roles of one of the major synovial fluid (SF) T cell subsets, V gamma 9(+)V delta 2(+) (V gamma 9(+)) T cells, in JIA. We found that as opposed to CD4(+) T cells, equally high percentages (similar to 35%) of V gamma 9(+) T cells in SF and peripheral blood (PB) produced TNF-alpha and IFN-gamma. Furthermore, stimulation with isopentenyl pyrophosphate (IPP), a metabolite in the mevalonate pathway, which is a specific potent Ag for V gamma 9J gamma 1.2(+) T cells, similarly amplified cytokine secretion by SF and PB V gamma 9(+) T cells. Significantly, the SF subset expressed higher levels of CD69 in situ, suggesting their recent activation. Furthermore, 24-h coculturing with SF-derived fibroblasts enhanced CD69 on the SF > PB V gamma 9(+) T cells, a phenomenon strongly augmented by zoledronate, a farnesyl pyrophosphate synthase inhibitor that increases endogenous intracellular IPP. Importantly, although V gamma 9(+) T cell proliferation in response to IPP was significantly lower in SF than PBMC cultures, it could be enhanced by depleting SF CD4(+)CD25(+)FOXP3(+) cells (regulatory T cells). Furthermore, coculture with the V gamma 9(+) T cells in medium containing zoledronate or IPP strongly increased SF-derived fibroblasts' apoptosis. The findings that IPP-responsive proinflammatory synovial V gamma 9(+) T cells for which proliferation is partly controlled by regulatory T cells can recognize and become activated by SF fibroblasts and then induce their apoptosis suggest their crucial role in the pathogenesis and control of synovial inflammation. The Journal of Immunology, 2012, 188: 4349-4359.