Murday Alanna S, Chaudhry Suchita, Pauza C David
Institute of Human Virology and Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
Immunology. 2017 Aug;151(4):385-394. doi: 10.1111/imm.12735. Epub 2017 May 24.
The study aimed to identify an immunoregulatory factor that restores the phosphoantigen response of Vγ9Vδ2 T cells from HIV-positive individuals on antiretroviral therapy. It was designed to characterize the effects of interleukin-18 (IL-18) on proliferation and effector function in Vγ9Vδ2 T cells from HIV-negative individuals and test whether exogenous IL-18 reconstitutes the Vγ9Vδ2 T-cell response to phosphoantigen from HIV-positive donors. Vγ9Vδ2 T cells from HIV-negative individuals responded strongly to phosphoantigen or aminobisphosphonate stimulation of peripheral blood mononuclear cells (PBMC), whereas cells with similar T-cell receptor profiles from HIV-positive individuals only responded to aminobisphosphonate. Interleukin-18 was higher after aminobisphosphonate stimulation due to activation of the inflammasome pathway. Both IL-18 and IL-18 receptor levels were measured and the activity of exogenous IL-18 on HIV-negative and HIV-positive PBMC was evaluated in terms of Vγ9Vδ2 T-cell proliferation, memory subsets, cytokine expression and CD107a expression. Interleukin-18 stimulation increased proliferation, enhanced the accumulation of effector memory cells, and increased expression of cytotoxic markers in HIV-negative controls. When Vγ9Vδ2 T cells from HIV-positive individuals were stimulated with isopentenyl pyrophosphate in the presence of IL-18, there was increased proliferation, accumulation of memory cells, and higher expression of CD56, NKG2D and CD107a (markers of cytotoxic effector phenotype). Interleukin-18 stimulation specifically expanded the Vγ9-JγP subset of Vγ9Vδ2 T cells, as was expected for normal responses to phosphoantigen. Interleukin-18 is a potent stimulator of Vγ9Vδ2 T-cell proliferation and effector function. Therapies directed at reconstituting Vγ9Vδ2 T-cell activity in HIV-positive individuals should include stimulators of IL-18 or direct cytokine supplementation.
该研究旨在确定一种免疫调节因子，该因子可恢复接受抗逆转录病毒治疗的HIV阳性个体的Vγ9Vδ2 T细胞的磷酸抗原反应。其旨在表征白细胞介素-18（IL-18）对HIV阴性个体的Vγ9Vδ2 T细胞增殖和效应功能的影响，并测试外源性IL-18是否能重建Vγ9Vδ2 T细胞对HIV阳性供体磷酸抗原的反应。HIV阴性个体的Vγ9Vδ2 T细胞对外周血单核细胞（PBMC）的磷酸抗原或氨基双膦酸盐刺激反应强烈，而来自HIV阳性个体的具有相似T细胞受体谱的细胞仅对氨基双膦酸盐有反应。由于炎性小体途径的激活，氨基双膦酸盐刺激后白细胞介素-18水平升高。测量了IL-18和IL-18受体水平，并根据Vγ9Vδ2 T细胞增殖、记忆亚群、细胞因子表达和CD107a表达评估了外源性IL-18对HIV阴性和HIV阳性PBMC的活性。白细胞介素-18刺激增加了HIV阴性对照中的增殖，增强了效应记忆细胞的积累，并增加了细胞毒性标志物的表达。当在IL-18存在下用异戊烯基焦磷酸刺激HIV阳性个体的Vγ9Vδ2 T细胞时，增殖增加、记忆细胞积累以及CD56、NKG2D和CD107a（细胞毒性效应表型标志物）的表达更高。白细胞介素-18刺激特异性地扩增了Vγ9Vδ2 T细胞的Vγ9-JγP亚群，这正如对磷酸抗原正常反应所预期的那样。白细胞介素-18是Vγ9Vδ2 T细胞增殖和效应功能的有效刺激剂。旨在重建HIV阳性个体中Vγ9Vδ2 T细胞活性的疗法应包括IL-18刺激剂或直接补充细胞因子。
