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.

Gamma delta T cells in non‐immune patients during primary schistosomal infection

“…On the other hand, the absence of systemic symptoms associated with a higher relative level of γδ T cells among the T cells in the peripheral blood, suggests that these cells may function to dampen the systemic acute inflammatory response engendered by the parasite, which is reminiscent of previous finding showing inverse relationship of γδ T cells and intensity of inflammation in juvenile idiopathic arthritis [27,28]. Recent studies suggest that γδ T cells could indeed suppress αβ T cells [29].…”

Dysregulated CD25 and Cytokine Expression by γδ T Cells of Systemic Sclerosis Patients Stimulated With Cardiolipin and Zoledronate

“…Peripheral blood mononuclear cells (PBMCs) were separated from 10 to 20 ml of heparinized blood on Lymphoprep gradients (AXIS-SHIEL, Oslo, Norway) by density centrifugation at 1,500 rpm as previously described (21). The mononuclear fraction was removed from the interface washed in phosphate-buffered saline (PBS) solution PH 7.4 and frozen in liquid nitrogen.…”

“…Cell staining procedures were as previously described (21). Lymphocytes were gated according to typical forward and side scatter plots using a BD FACS Calibur flow cytometer (Becton Dickinson, Mountain View CA, USA), and analysis of gated cells was performed using FlowJo software.…”

What rheumatologists need to know about innate lymphocytes

“…Together, such findings warrant further investigation of the CD1d-restricted NKT cell populations in the context of autoimmune disease in general 11 . contribute to TNF-α and IFN-γ production in the joint 89 and others suggesting that there is a change in the proportion of subtypes of γδ T cells in RA patients with Vγ2Vδ2 T cells being protective and Vγ1Vδ1 T cells contributing to pathogenesis 90 . Clearly more work is needed to determine exactly which γδ T cell subtypes are immune-protective and which contribute towards autoimmunity before γδ T cell therapies can be developed.…”