Cellular Interactions of Synovial Fluid gamma delta 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.