Oxidative stress by tumor-derived macrophages suppresses the expression of CD3 ζ chain of T-cell receptor complex and antigen-specific T-cell responses

One of the important mechanisms of immunosuppression in the tumor-bearing status has been attributed to the down-modulation of the CD3 ζ chain and its associated signaling molecules in T cells. Thus, the mechanism of the disappearance of CD3ζ was investigated in tumor-bearing mice (TBM). The decrease of CD3ζ was observed both in the cell lysate and intact cells. Direct interaction of T cells with macrophages from TBM (TBM-macrophages) induced the decrease of CD3ζ, and depletion of macrophages rapidly restored the CD3ζ expression. We found that treatment of such macrophages with N-acetylcysteine, known as antioxidant compound, prevented the decrease of CD3ζ. Consistent with this result, the addition of oxidative reagents such as hydrogen peroxide and diamide induced the decrease of CD3ζ expression in T cells. Consequently, the loss of CD3ζ resulted in suppression of the antigen-specific T-cell response. These results demonstrate that oxidative stress by macrophages in tumor-bearing status induces abnormality of the T-cell receptor complex by cell interactions with T cells. Therefore, our findings suggest that oxidative stress contributes to the regulation of the expression and function of the T-cell receptor complex.

荷瘤状态下机体免疫抑制的重要机制之一，被归因于T细胞中CD3 ζ链及其相关信号分子的表达下调。为此，本研究针对荷瘤小鼠（tumor-bearing mice, TBM）体内CD3ζ的表达缺失机制展开探究。研究人员在细胞裂解液与完整细胞中均检测到CD3ζ的表达下调。T细胞与荷瘤小鼠来源的巨噬细胞（TBM-macrophages）直接相互作用，可诱导CD3ζ表达下调；而巨噬细胞耗竭则能快速恢复CD3ζ的表达水平。本研究发现，使用公认的抗氧化剂N-乙酰半胱氨酸（N-acetylcysteine）处理上述巨噬细胞，可阻断CD3ζ的表达下调。与此结果一致，向T细胞中添加过氧化氢（hydrogen peroxide）、二酰胺（diamide）等氧化试剂，同样可诱导T细胞内CD3ζ的表达下调。综上，CD3ζ的缺失会抑制抗原特异性T细胞应答。上述结果表明，荷瘤状态下巨噬细胞介导的氧化应激可通过与T细胞的相互作用，诱导T细胞受体复合物异常。因此，本研究结果提示，氧化应激参与调控T细胞受体复合物的表达与功能。