Interleukin 4 (IL-4) has a variety of immune functions, including helper T-cell (Th-cell) differentiation and innate immune-response processes. However, the impact of IL-4 on gamma delta (cd) T cells remains unclear. In this study, we investigate the effects of IL-4 on the activation and proliferation of cd T cells and the balance between variable delta 1 (Vd1) and Vd2 T cells in humans. The results show that IL-4 inhibits the activation of cd T cells in the presence of cd T-cell receptor (TCR) stimulation in a STAT6-dependent manner. IL-4 promoted the growth of activated cd T cells and increased the levels of Vd1 T cells, which in turn inhibited Vd2 T-cell growth via significant IL-10 secretion. Vd1 T cells secreted significantly less interferon gamma (IFNc) and more IL-10 relative to Vd2. Furthermore, Vd1 T cells showed relatively low levels of Natural Killer Group 2D (NKG2D) expression in the presence of IL-4, suggesting that Vd1 T cells weaken the cd T cell-mediated anti-tumor immune response. For the first time, our findings demonstrate a negative regulatory role of IL-4 in cd T cell-mediated anti-tumor immunity. Cellular & Molecular Immunology

ObjectivesTo explore the role of Vδ2 T cells in the pathogenesis of rheumatoid arthritis (RA).MethodsSixty-eight patients with RA, 21 patients with osteoarthritis and 21 healthy controls were enrolled in the study. All patients with RA fulfilled the 2010 American College of Rheumatology/European League Against Rheumatism criteria for RA. Peripheral Vδ2T population, chemokine receptor expression and proinflammatory cytokine secretion were quantified by flow cytometry. The infiltration of Vδ2 T cells within the synovium was examined by immunohistochemistry and flow cytometry. The effect of tumour necrosis factor (TNF)-α and interleukin (IL)-6 on Vδ2 T migration was determined by flow cytometry and transwell migration assay.ResultsPeripheral Vδ2T cells, but not Vδ1 T cells, were significantly lower in patients with RA, which was negatively correlated with disease activity gauged by Disease Activity Score in 28 joints. Vδ2 T cells from RA accumulated in the synovium and produced high levels of proinflammatory cytokines including interferon-γ and IL-17. Phenotypically, Vδ2 T cells from RA showed elevated chemotaxis potential and expressed high levels of chemokine receptors CCR5 and CXCR3, which was driven by increased serum TNF-α through nuclear factor kappa B signalling. In vivo, TNF-α neutralising therapy dramatically downregulated CCR5 and CXCR3 on Vδ2 T cells and repopulated the peripheral Vδ2 T cells in patients with RA.ConclusionsHigh levels of TNF-α promoted CCR5 and CXCR3 expression in Vδ2 T cells from RA, which potentially infiltrated into the synovium and played crucial roles in the pathogenesis of RA. Targeting Vδ2 T cells might be a potential approach for RA.

Background: TCR␥␦ and NKG2D are two important receptors for ␥␦T cell cytotoxicity. Results: ␥␦T cell cytotoxicity is TCR␥␦-dependent and requires the activation of Vav1-PLC-␥1 pathway. Conclusion: ␥␦T cell cytotoxicity requires a strong signal to overcome the inhibitory threshold set by Cbl-b. Significance: Our finding provides new insights into the molecular mechanisms underlying the activation of ␥␦T cell cytotoxicity.

In this study, we measured the proportion of peripheral Vδ2 T cells as well as the status and chemokine receptor expression profiles in SLE patients and healthy control (HC). In addition, Vδ2 T cell infiltration in the kidneys of patients with lupus nephritis was examined. The results showed that the percentage of peripheral Vδ2 T cells in new-onset SLE was decreased, and negatively correlated with the SLE Disease Activity Index score and the severity of proteinuria. These cells had a decreased apoptosis but an increased proliferation, and they showed increased accumulation in SLE kidneys. Moreover, IL-21 production and CD40L, CCR4, CCR7, CCR8, CXCR1 and CX3CR1 expression in Vδ2 T cells from SLE patients was significantly higher than from HC (p < 0.05), and these factors were downregulated in association with the repopulation of peripheral Vδ2 T cells in patients who were in remission (p < 0.05). In addition, anti-TCR Vδ2 antibodies activation significantly upregulated these chemokine receptors on Vδ2 T cells from HC, and this effect was blocked by inhibitors of PLC-γ1, MAPK/Erk, and PI3K signaling pathways. Our findings demonstrate that the distribution and function status of Vδ2 T cells from SLE patients are abnormal, and these aberrations may contribute to disease pathogenesis.

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