Alleva D G, Burger C J, Elgert K D
Department of Biology, Virginia Polytechnic Institute and State University, Blacksburg 24061-0406.
Scand J Immunol. 1994 Jan;39(1):31-8. doi: 10.1111/j.1365-3083.1994.tb03336.x.
Normal immune homeostasis is regulated partly by a small population of CD4+ T cells that react to autologous major histocompatibility complex class-II molecules on self-cells. Decreased autoreactive T-cell responses are associated with cancer. Tumour growth causes syngeneic macrophages (M phi) to suppress autoreactive T-cell proliferation by decreasing M phi class-II expression and increasing M phi production of the suppressor molecule prostaglandin E2 (PGE2). Because interferon-gamma (IFN-gamma) is a potent M phi activation molecule which regulates both M phi PGE2 and class-II expression, the effects of IFN-gamma on tumour-induced suppression of autoreactive T-cell proliferation were investigated. Exogenous IFN-gamma increased normal host (NH) CD4+ autoreactive T-cell proliferation stimulated by syngeneic NH M phi but decreased proliferation stimulated by tumour-bearing host (TBH) M phi. Antibody (Ab) neutralization of endogenous IFN-gamma activity reduced TBH M phi-mediated suppression. Kinetic studies showed that endogenous IFN-gamma suppressor activity was not exclusive during T-cell activation. Indomethacin treatment blocked IFN-gamma-induced suppression in TBH M phi-T cell cultures. TBH M phi-T cell cultures contained significantly more PGE2 than those containing NH M phi. Exogenous IFN-gamma increased early PGE2 production in TBH M phi cultures but decreased production in NH M phi cultures. The Ab-mediated neutralization of endogenous transforming growth factor-beta or tumour necrosis factor-alpha reduced TBH M phi-mediated suppression and blocked IFN-gamma-induced suppression. Short-term treatment of M phi with IFN-gamma before their addition to T cells caused TBH M phi to stimulate T-cell proliferation, which suggests that early suppressor molecule production by TBH M phi inhibits synthesis or activity of IFN-gamma-induced stimulatory monokines. These results show that tumour growth causes M phi to suppress autoreactive T-cell responses by allowing IFN-gamma to induce M phi suppressor molecules, which block production or activity of stimulatory monokines.
正常免疫稳态部分由一小群对自身细胞上的自体主要组织相容性复合体II类分子产生反应的CD4+ T细胞调节。自身反应性T细胞反应降低与癌症相关。肿瘤生长导致同基因巨噬细胞（M phi）通过降低M phi II类表达和增加抑制分子前列腺素E2（PGE2）的M phi产生来抑制自身反应性T细胞增殖。由于干扰素-γ（IFN-γ）是一种有效的M phi激活分子，可调节M phi PGE2和II类表达，因此研究了IFN-γ对肿瘤诱导的自身反应性T细胞增殖抑制的影响。外源性IFN-γ增加了同基因正常宿主（NH）M phi刺激的正常宿主（NH）CD4+自身反应性T细胞增殖，但降低了荷瘤宿主（TBH）M phi刺激的增殖。内源性IFN-γ活性的抗体（Ab）中和降低了TBH M phi介导的抑制作用。动力学研究表明，内源性IFN-γ抑制活性在T细胞激活过程中并非排他性的。吲哚美辛处理阻断了TBH M phi-T细胞培养物中IFN-γ诱导的抑制作用。TBH M phi-T细胞培养物中含有的PGE2明显多于含有NH M phi的培养物。外源性IFN-γ增加了TBH M phi培养物中早期PGE2的产生，但降低了NH M phi培养物中的产生。Ab介导的内源性转化生长因子-β或肿瘤坏死因子-α的中和降低了TBH M phi介导的抑制作用，并阻断了IFN-γ诱导的抑制作用。在将M phi添加到T细胞之前用IFN-γ对其进行短期处理导致TBH M phi刺激T细胞增殖，这表明TBH M phi早期产生的抑制分子抑制了IFN-γ诱导的刺激单核因子的合成或活性。这些结果表明，肿瘤生长导致M phi通过允许IFN-γ诱导M phi抑制分子来抑制自身反应性T细胞反应，这些抑制分子阻断刺激单核因子的产生或活性。
