Darji A, Beschin A, Sileghem M, Heremans H, Brys L, De Baetselier P
Unit of Cellular Immunology, Flemish Interuniversity Institute of Biotechnology, University of Brussels (V.U.B.), Sint Genesius Rode, Belgium.
Infect Immun. 1996 Jun;64(6):1937-43. doi: 10.1128/iai.64.6.1937-1943.1996.
Experimental infections of mice with the African trypanosome Trypanosoma brucei lead to a profound state of T-cell unresponsiveness in the lymph node cell (LNC) compartment. This suppression is mediated by macrophage-like cells which inhibit interleukin 2 (IL-2) secretion and down-regulate IL-2 receptor expression (M. Sileghem, A. Darji, R. Hamers, M. Van de Winkel, and P. De Baetselier, Eur. J. Immunol. 19:829-835, 1989). Similar suppressive cells can be generated in vitro by pulsing 2C11-12 macrophage hybridoma cells with opsonized T. brucei parasites (2C11-12P cells). Cocultures of 2C11-12P cells and LNCs secrete higher levels of gamma interferon (IFN-gamma), and the hyperproduction of IFN-gamma was found to be confined to CD8+ lymphoid cells. Elimination of CD8+ cells from cocultures of 2C11-12P cells and LNCs restores the T-cell proliferative response. Furthermore, addition of neutralizing anti-IFN-gamma antibodies to the cocultures reduces the level of suppression and concomitantly restores the level of IL-2 receptor expression. Hence, IFN-gamma plays a cardinal role in this in vitro model for T. brucei-elicited immunosuppression. Cocultures of LNCs and 2C11-12P cells in a two-chamber culture system further demonstrated that cell-cell contact is required for hyperproduction of IFN-gamma and, moreover, that IFN-gamma cooperates with a 2C11-12P-derived diffusible factor to exert its suppressive activity. Finally, tumor necrosis factor alpha (TNF-alpha produced by 2C11-12P cells was found to be implicated in the hyperproduction of IFN-gamma, since addition of neutralizing anti-TNF-alpha antibodies to cocultures reduced the level of suppression and concomitantly abrogated the hyperproduction of IFN-gamma. Collectively, our findings indicate that T. brucei-elicited suppressive 2C11-12 macrophage cells differentially influence T-cell subpopulations: (i) CD8+ cells are signaled via cell-cell contact to produce IFN-gamma, and TNF-alpha is implicated in this process, and (ii) locally produced IFN-gamma and macrophage-released factors act in concert to inhibit CD4+ and CD8+ T-cell proliferative responses.
用非洲锥虫布氏锥虫对小鼠进行实验性感染，会导致淋巴结细胞（LNC）区室出现深度T细胞无反应状态。这种抑制作用由类似巨噬细胞的细胞介导，这些细胞抑制白细胞介素2（IL-2）的分泌并下调IL-2受体的表达（M. 西莱格姆、A. 达吉、R. 哈默斯、M. 范德温克尔和P. 德贝茨利尔，《欧洲免疫学杂志》19:829 - 835，1989年）。通过用调理过的布氏锥虫寄生虫脉冲处理2C11 - 12巨噬细胞杂交瘤细胞（2C11 - 12P细胞），可在体外产生类似的抑制性细胞。2C11 - 12P细胞与LNC的共培养物分泌更高水平的γ干扰素（IFN - γ），并且发现IFN - γ的过量产生仅限于CD8 + 淋巴细胞。从2C11 - 12P细胞与LNC的共培养物中去除CD8 + 细胞可恢复T细胞增殖反应。此外，向共培养物中添加中和性抗IFN - γ抗体可降低抑制水平，并同时恢复IL - 2受体表达水平。因此，IFN - γ在这种布氏锥虫引发的免疫抑制体外模型中起关键作用。在双室培养系统中LNC与2C11 - 12P细胞的共培养进一步证明，细胞间接触是IFN - γ过量产生所必需的，而且，IFN - γ与2C11 - 12P衍生的可扩散因子协同发挥其抑制活性。最后，发现2C11 - 12P细胞产生的肿瘤坏死因子α（TNF - α）与IFN - γ的过量产生有关，因为向共培养物中添加中和性抗TNF - α抗体可降低抑制水平，并同时消除IFN - γ的过量产生。总体而言，我们的研究结果表明，布氏锥虫引发的抑制性2C11 - 12巨噬细胞对T细胞亚群有不同影响：（i）CD8 + 细胞通过细胞间接触被信号传导以产生IFN - γ，TNF - α参与此过程，（ii）局部产生的IFN - γ和巨噬细胞释放的因子协同作用以抑制CD4 + 和CD8 + T细胞增殖反应。
