Cellular interactions of synovial fluid γδ T cells in juvenile idiopathic arthritis

Anna Bendersky, Victoria Marcu-Malina, Yackov Berkun, Maya Gerstein, Meital Nagar, Itamar Goldstein, Shai Padeh, Ilan Bank

Research output: Contribution to journalArticlepeer-review

Abstract

The pathogenesis of juvenile idiopathic arthritis (JIA) is thought to involve multiple components of the cellular immune system, including subsets of γδ T cells. In this study, we conducted experiments to define the functional roles of one of the major synovial fluid (SF) T cell subsets, Vγ9 +Vδ2 + (Vγ9 +) T cells, in JIA. We found that as opposed to CD4 + T cells, equally high percentages (∼35%) of Vγ9 + T cells in SF and peripheral blood (PB) produced TNF-α and IFN-γ. Furthermore, stimulation with isopentenyl pyrophosphate (IPP), a metabolite in the mevalonate pathway, which is a specific potent Ag for Vγ9Jγ1.2 + T cells, similarly amplified cytokine secretion by SF and PB Vγ9 + 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 Vγ9 + T cells, a phenomenon strongly augmented by zoledronate, a farnesyl pyrophosphate synthase inhibitor that increases endogenous intracellular IPP. Importantly, although Vγ9 + 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 Vγ9 + T cells in medium containing zoledronate or IPP strongly increased SF-derived fibroblasts' apoptosis. The findings that IPP-responsive proinflammatory synovial Vγ9 + 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.

Original languageEnglish
Pages (from-to)4349-4359
Number of pages11
JournalJournal of Immunology
Volume188
Issue number9
DOIs
StatePublished - 1 May 2012

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