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

Abstract

Objectivesγδ T cells, a non-conventional innate lymphocyte subset containing cells that can be activated by lipids and phosphoantigens, are abnormally regulated in systemic sclerosis (SSc). To further evaluate the significance of this dysregulation, we compared how exposure to an autoantigenic lipid, cardiolipin (CL), during co-stimulation with an amino-bisphosphonate (zoledronate, zol), affects the activation and cytokine production of SSc and healthy control (HC) γδ T cells.MethodsExpression of CD25 on Vγ9+, Vδ1+, and total CD3+ T cells in cultured peripheral blood mononuclear cells (PBMCs), their binding of CD1d tetramers, and the effect of monoclonal antibody (mAb) blockade of CD1d were monitored by flow cytometry after 4 days of in vitro culture. Intracellular production of IFNγ and IL-4 was assessed after overnight culture.ResultsPercentages of CD25+ among CD3+ and Vδ1+ T cells were elevated significantly in short-term cultured SSc PBMC compared to HC. In SSc but not HC, CL and zol, respectively, suppressed %CD25+ Vγ9+ and Vδ1+ T cells but, when combined, CL + zol significantly activated both subsets in HC and partially reversed inhibition by the individual reagents in SSc. Importantly, Vδ1+ T cells in both SSc and HC were highly reactive with lipid presenting CD1d tetramers, and a CD1d-blocking mAb decreased CL-induced enhancement of %SSc CD25+ Vδ1+ T cells in the presence of zol. %IFNγ+ cells among Vγ9+ T cells of SSc was lower than HC cultured in medium, CL, zol, or CL + zol, whereas %IFNγ+ Vδ1+ T cells was lower only in the presence of CL or CL + zol. %IL-4+ T cells were similar in SSc and HC in all conditions, with the exception of being increased in SSc Vγ9+ T cells in the presence of CL.ConclusionAbnormal functional responses of γδ T cell subsets to stimulation by CL and phosphoantigens in SSc may contribute to fibrosis and immunosuppression, characteristics of this disease.

T Cells in Fibrosis and Fibrotic Diseases

“…The level of pathogenic CD27 + γδ T cells were reported to increase, with upregulation of granzyme B or perforin expression (134). Further, Vγ9Vδ2, a subset of human γδ T cells, shows anti-fibrotic potential with the production of IFNγ (135,136). An abundance of approximately 8-20% γδ T cells in resident pulmonary lymphocytes shows the possible engagement of γδ T cells in lung infection, chronic inflammation, and subsequent pulmonary fibrosis (137).…”

“…Further, it has been reported that skin fibroblasts exhibit higher proliferative activity and stronger collagen synthesis ability when cultured with γδ T cell supernatant ( 133 ). Studies on patients with systemic sclerosis have demonstrated the involvement of γδ T cells ( 134 – 136 ). The level of pathogenic CD27 + γδ T cells were reported to increase, with upregulation of granzyme B or perforin expression ( 134 ).…”

“…The level of pathogenic CD27 + γδ T cells were reported to increase, with upregulation of granzyme B or perforin expression ( 134 ). Further, Vγ9Vδ2, a subset of human γδ T cells, shows anti-fibrotic potential with the production of IFNγ ( 135 , 136 ).…”

Unraveling the Link Between Mitochondrial Dynamics and Neuroinflammation

“…Interestingly, a subset of Gamma-delta T cells (Tγδ) increased in Multiple Sclerosis (MS) patients has been shown to be activated by cardiolipin. Although their exact role is still not clear, it suggests an important role for cardiolipin also activating adaptive immune responses during CNS disease progression ( 81 ).…”

The Role of Gamma Delta T Cells in Autoimmune Rheumatic Diseases

“…CL also decreased IFNγ secretion of SSc Vδ1 + T cells relative to HC. Thus, CD1d mediated interactions of Vδ1 + T cells in SSc may play a profibrotic role via effects on pro and anti fibrotic cytokines, in particular in the context of simultaneous Vγ9 + T cell triggering [109].…”