Suppressor macrophages in African trypanosomiasis inhibit T cell proliferative responses by nitric oxide and prostaglandins.
Suppressor macrophages in African trypanosomiasis inhibit T cell proliferative responses by nitric oxide and prostaglandins.
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DOI：
10.4049/jimmunol.151.10.5492
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发表时间：
1993-11
影响因子：
4.4
通讯作者：
K. Schleifer;J. M. Mansfield
中科院分区：
文献类型：
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作者：
K. Schleifer;J. M. Mansfield
宿主 T 细胞反应的抑制是非洲锥虫感染的标志之一。免疫抑制的细胞基础包括抑制性巨噬细胞的产生，其下调 T 细胞增殖，但不一定下调细胞因子对丝裂原和锥虫 Ag 的反应。由于来自受感染动物的巨噬细胞表现出激活特征，我们询问激活细胞的产物，特别是一氧化氮 (NO) 和 PG，是否可以介导观察到的抑制细胞效应和免疫抑制。我们证明，从感染罗得西亚布氏锥虫的 B10.BR 小鼠中分离的细胞表现出诱导型 NO 合酶的转录上调，并释放大量 NO。用T细胞有丝分裂原或特定寄生虫Ag刺激细胞后，释放的NO水平进一步升高；抗体阻断实验表明，NO 合成的上调至少部分依赖于 IFN-γ 和 TNF-α。向细胞培养物中添加诱导型 NO 合酶底物类似物（例如 NG-单甲基-L-精氨酸）可抑制 NO 释放，并部分逆转此类培养物所表现出的抑制细胞活性和免疫抑制作用。受感染小鼠的细胞培养物中 PG 水平也有所升高，但 PG 抑制剂吲哚美辛单独添加到培养物中时对抑制细胞或抑制没有影响。然而，通过添加 NG-单甲基-L-精氨酸和吲哚美辛同时抑制 NO 和 PG 合成，完全阻断了与感染巨噬细胞相关的抑制细胞活性，并导致感染细胞进一步从免疫抑制中恢复，从而揭示了这两种介质之间的上位效应。我们得出的结论是，锥虫病中巨噬细胞的激活会诱导活性氮中间体和 PG 的释放，从而下调感染期间 T 细胞的增殖反应。
Suppression of host T cell responses is one of the hallmarks of infection with the African trypanosomes. The cellular basis for immunosuppression includes the generation of suppressor macrophages that down-regulate T cell proliferative but not necessarily cytokine responses to both mitogen and trypanosome Ag. Since macrophages from infected animals display activation characteristics, we have asked whether products of activated cells, specifically nitric oxide (NO) and PG, may mediate the suppressor cell effects and immunosuppression observed. We demonstrate that cells isolated from B10.BR mice infected with Trypanosoma brucei rhodesiense exhibited transcriptional up-regulation of inducible NO synthase and released significant amounts of NO. The levels of NO released were elevated further after stimulation of cells with T cell mitogens or specific parasite Ag; antibody blocking experiments demonstrated that this up-regulation of NO synthesis was at least partially dependent upon IFN-gamma and TNF-alpha. The addition of inducible NO synthase substrate analogues such as NG-monomethyl-L-arginine to cell cultures inhibited NO release and also partially reversed the suppressor cell activity and immunosuppression displayed by such cultures. PG levels also were elevated in cell cultures from infected mice, but the PG inhibitor indomethacin had no effect on suppressor cells or suppression when added alone to the cultures. However, the concurrent inhibition of NO and PG synthesis by the addition of both NG-monomethyl-L-arginine and indomethacin completely blocked suppressor cell activity associated with infected macrophages and also resulted in further recovery of infected cells from immunosuppression, thus revealing an epistatic effect between these two mediators. We conclude that macrophage activation in trypanosomiasis induces the release of reactive nitrogen intermediates and PG, which down-regulate proliferative responses by T cells during infection.