CD8^(+)T细胞功能耗竭与继发性噬血细胞综合征发病的关系及其机制研究

Exhaustion of CD8^(+)T Lymphocytes Plays a Critical Role in the Pathogenesis of Secondary Hemophagocytic Lymphohistiocytosis

目的:探讨CD8^(+)T细胞功能变化在继发性噬血细胞综合征(sHLH)发病过程中的作用和意义,揭示sHLH可能的发病机制。方法:流式细胞术检测sHLH患者CD8^(+)T细胞耗竭标记PD-1、TIM-3和LAG-3的表达,ΔCD107a表达和细胞内干扰素γ(IFN-γ)分泌水平,检测效应记忆CD8^(+)T细胞、调节性T细胞及双阴性T细胞的数量。结果:sHLH患者CD8^(+)T细胞上抑制性受体PD-1、TIM-3和LAG-3的表达水平分别为40.73±22.64、15.97±14.45和0.73(0-37.41),明显高于对照组的14.48±7.98、1.95±1.52和0.01(0-2),差异均有统计学意义(P<0.001);而CD8^(+)T细胞的ΔCD107a表达量(4.49±2.71 vs 6.07±2.14,P=0.035)和IFN-γ分泌水平(37.30±24.46 vs 55.17±22.23,P=0.034)则明显低于对照组。sHLH患者效应记忆性CD8^(+)T细胞的数量明显少于对照组(14.35±10.37 vs 22.92±11.12,P=0.016),而调节性T细胞及双阴性T细胞数量则无明显差异。sHLH患者活动期CD8^(+)T的PD-1、TIM-3和LAG-3表达量分别为38.09±21.87、14.35±13.70和0.82(0-13.22),明显高于缓解期的24.27±17.23(P=0.03)、8.64±5.60(P=0.014)和0.13(0-3.69)(P=0.043)。结论:CD8^(+)T细胞功能耗竭可能是参与sHLH发生的重要环节之一。

Objective:To investigate the changes in function of CD8^(+)T cell subsets,and explore its significance in pathogenesis of secondary hemophagocytic lymphohistiocytosis(sHLH).Methods:Flow cytometry was used to detect the expressions of PD-1,TIM-3,and LAG-3,which were the markers of exhausted CD8^(+)T cell,as well as the secretion levels of interferon γ(IFN-γ) and expression of Δ CD 107 a after the stimulation;the numbers of effector-memory CD8^(+)T cells,regulatory T cells and double negative T cells were also detected.Results:The expressions of inhibitory receptors(PD-1,TIM3 and LAG-3) on CD8^(+)T cells of sHLH patients were 40.73±22.64,15.97±14.45 and 0.73(0-37.41),respectively,which were significantly higher than those of the control group(P<0.001).In contrast,the expression ofΔCD107 a(4.49±2.71 vs 6.07±2.14,P=0.035) and secretion level of IFN-γ(37.30±24.46 vs 55.17±22.23,P=0.034)were significantly lower.The number of effector-memory CD8^(+)T cells in sHLH patients was also lower as compared with that in control group(14.35±10.37 vs 22.92±11.12,P=0.016).But there was no significant difference in the number of regulatory T cell and double negative T cell.In addition,the expressions of PD-1,TIM3 and LAG-3 in active stage of sHLH were 38.09±21.87,14.35±13.70 and 0.82(0-13.22),respectively,which were significant higher than those in remission stage [24.27±17.23(P=0.03),8.64±5.60(P=0.014) and 0.13(0-3.69)].Conclusion:The exhausted CD8^(+)T lymphocytes may play a critical role in the development of sHLH.