title: Cellular interactions of synovial fluid γδ T cells in juvenile idiopathic arthritis.
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.
authors.affiliation: Laboratory of Immunoregulation, Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: Anna
authors.initials: A
authors.lastname: Bendersky
authors.forename: Victoria
authors.initials: V
authors.lastname: Marcu-Malina
authors.forename: Yackov
authors.initials: Y
authors.lastname: Berkun
authors.forename: Maya
authors.initials: M
authors.lastname: Gerstein
authors.forename: Meital
authors.initials: M
authors.lastname: Nagar
authors.forename: Itamar
authors.initials: I
authors.lastname: Goldstein
authors.forename: Shai
authors.initials: S
authors.lastname: Padeh
authors.forename: Ilan
authors.initials: I
authors.lastname: Bank
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D001171:Arthritis, Juvenile / Q000276:immunology* / Q000473:pathology; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D002450:Cell Communication / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D018920:Coculture Techniques; D004164:Diphosphonates / Q000276:immunology / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000276:immunology* / Q000473:pathology; D051228:Geranyltranstransferase / Q000037:antagonists & inhibitors / Q000276:immunology; D045782:Hemiterpenes / Q000276:immunology; D006801:Humans; D007093:Imidazoles / Q000276:immunology / Q000494:pharmacology; D007371:Interferon-gamma / Q000276:immunology; D037181:Lectins, C-Type / Q000276:immunology; D008297:Male; D009943:Organophosphorus Compounds / Q000276:immunology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D013582:Synovial Fluid / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D000077211:Zoledronic Acid; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D051228:Geranyltranstransferase; D045782:Hemiterpenes; D007093:Imidazoles; D007371:Interferon-gamma; D037181:Lectins, C-Type; D009943:Organophosphorus Compounds; D016692:Receptors, Antigen, T-Cell, gamma-delta; D014409:Tumor Necrosis Factor-alpha; D000077211:Zoledronic Acid; D000099192:CD69 Antigens; C004809:isopentenyl pyrophosphate