Kierszenbaum F, Moretti E, Sztein M B
Department of Microbiology and Public Health, Michigan State University, East Lansing 48824, USA.
Biol Res. 1993;26(1-2):197-207.
The mechanisms by which Trypanosoma cruzi causes dysfunction in normal human lymphocytes was studied by using an in vitro system in which purified parasites and normal peripheral blood mononuclear cells are co-cultured in the presence or absence of mitogens. Our results have shown that T. cruzi impairs the expression of receptors for interleukin-2 (IL-2R) and transferrin, activated lymphocyte membrane molecules which play key roles in controlling progression through the cell cycle. T. cruzi also downregulates the expression of constitutive lymphocyte molecules (e.g., CD4, and CD8) involved in the interactions between antigen-presenting cells and T lymphocytes as well as the expression of T cell receptor (TCR) and CD3 molecules. The latter molecular structures are physically associated and are responsible for signaling and transducing activation events resulting from antigen binding. Stimulated B lymphocytes also display reduced IL-2R expression in the presence of T. cruzi. In contrast, neither the expression of EA-1 molecules by T lymphocytes nor that of CD19 and CD20 molecules by B lymphocytes is affected by this parasite. Thus, the T. cruzi effects are selective, not indiscriminate. The activated T cell populations affected by T. cruzi show concomitant reductions in the levels of expression of IL-2R and CD4, IL-2R and CD8, IL-2R and CD3 or IL-2R and TCR as well as in their capacity to proliferate; 3H-thymidine uptake decreases and there is a massive arrest of cells at the G0/G1a phase of the cell cycle. The immunosuppressive effects of T. cruzi are reproduced by a protein molecule(s) released spontaneously by the parasite termed TIF (for trypanosomal immunosuppressive factor). We report herein that TIF does not compete with IL-2 for binding to IL-2R and that shedding of IL-2R is decreased in the presence of T. cruzi. Moreover, the intracellular level of IL-2R was found to be lower than that found in control cells cultured in the absence of parasites. These results suggest that suppressed IL-2R reflects a modification induced by T. cruzi at a time coinciding with or preceding IL-2R mRNA translation. Studies are underway to identify the earliest process targeted by T. cruzi.
利用一种体外系统研究了克氏锥虫导致正常人淋巴细胞功能障碍的机制，该系统中在有丝分裂原存在或不存在的情况下将纯化的寄生虫与正常外周血单个核细胞共培养。我们的结果表明，克氏锥虫损害白细胞介素-2（IL-2R）和转铁蛋白受体的表达，这些活化的淋巴细胞膜分子在控制细胞周期进程中起关键作用。克氏锥虫还下调参与抗原呈递细胞与T淋巴细胞相互作用的组成性淋巴细胞分子（如CD4和CD8）的表达以及T细胞受体（TCR）和CD3分子的表达。后两种分子结构在物理上相关联，并负责由抗原结合引起的信号传导和转导激活事件。在克氏锥虫存在的情况下，受刺激的B淋巴细胞也显示出IL-2R表达降低。相比之下，T淋巴细胞EA-1分子的表达以及B淋巴细胞CD19和CD20分子的表达均不受该寄生虫影响。因此，克氏锥虫的作用是选择性的，而非无差别性的。受克氏锥虫影响的活化T细胞群体显示IL-2R与CD4、IL-2R与CD8、IL-2R与CD3或IL-2R与TCR表达水平同时降低，以及它们的增殖能力降低；3H-胸腺嘧啶摄取减少，并且大量细胞停滞在细胞周期的G0/G1a期。克氏锥虫的免疫抑制作用可由该寄生虫自发释放的一种蛋白质分子TIF（锥虫免疫抑制因子）重现。我们在此报告，TIF不与IL-2竞争结合IL-2R，并且在克氏锥虫存在的情况下IL-2R的脱落减少。此外，发现IL-2R的细胞内水平低于在无寄生虫培养的对照细胞中发现的水平。这些结果表明，IL-2R受抑制反映了克氏锥虫在与IL-2R mRNA翻译同时或之前诱导的一种修饰。正在进行研究以确定克氏锥虫靶向的最早过程。
