Alleva D G, Elgert K D
Department of Biology, Virginia Polytechnic Institute and State University, Blacksburg, USA.
Immunobiology. 1995 Feb;192(3-4):155-71. doi: 10.1016/S0171-2985(11)80094-X.
CD4+ autoreactive T cells are a major cell population in regulating immune responses to altered autologous neoplastic cells. Normal autoreactive T cells recognize major histocompatibility complex (MHC) class II molecules in association with self-peptides on antigen-presenting cells, such as macrophages (M phi). Tumor-bearing hosts (TBH) have decreased autoreactivity partly because tumors increase M phi secretion of suppressor molecules like prostaglandin E2 (PGE2) and decrease M phi MHC class II expression. Because interleukin (IL)-10, a cytokine produced by T cells, M phi, and tumor cells, inhibits production of most M phi suppressor molecules, we determined if IL-10 could reverse tumor-induced murine splenic M phi-mediated suppression of autoreactive T cell proliferation. Tumor growth enhanced activated M phi production of PGE2, nitric oxide, and tumor necrosis factor-alpha (TNF-alpha). IL-10 strongly reduced or inhibited M phi production of these molecules. When added to pure normal host (NH) CD4+ T cells, NH syngeneic splenic M phi stimulated autoreactive T cell proliferation more than did TBH splenic M phi. Exogenous IL-10 or M phi preincubation with IL-10 restored TBH M phi-stimulated autoreactivity to normal levels. IL-10 treatment had little or no effect on NH M phi-stimulated autoreactivity. IL-10 inhibited TBH M phi secretion of suppressor molecules in T cell proliferation assays because supernatants from IL-10-pretreated TBH M phi-syngeneic NH T cell cultures had decreased levels of suppressor molecules. When endogenous IL-10 activity was neutralized with anti-IL-10 monoclonal antibody, autoreactive T cell proliferation stimulated by NH or TBH M phi was slightly, but significantly decreased. Although IL-10 is known to inhibit M phi foreign antigen-presenting cell-dependent T cell proliferation, this study shows that IL-10 restores autoreactive T cell functions during tumor growth by counteracting M phi production of inhibitory molecules. These data suggest that IL-10 up-regulates anti-cancer autoreactive T cell responses by down-regulating suppressor M phi activity.
CD4+自身反应性T细胞是调节对改变的自体肿瘤细胞免疫反应的主要细胞群体。正常的自身反应性T细胞识别与抗原呈递细胞（如巨噬细胞，Mφ）上的自身肽相关的主要组织相容性复合体（MHC）II类分子。荷瘤宿主（TBH）的自身反应性降低，部分原因是肿瘤增加了Mφ分泌抑制分子，如前列腺素E2（PGE2），并降低了Mφ的MHC II类表达。由于白细胞介素（IL）-10是一种由T细胞、Mφ和肿瘤细胞产生的细胞因子，可抑制大多数Mφ抑制分子的产生，因此我们确定IL-10是否能逆转肿瘤诱导的小鼠脾脏Mφ介导的对自身反应性T细胞增殖的抑制。肿瘤生长增强了活化的Mφ产生PGE2、一氧化氮和肿瘤坏死因子-α（TNF-α）。IL-10强烈降低或抑制了Mφ对这些分子的产生。当添加到纯正常宿主（NH）的CD4+T细胞中时，NH同基因脾脏Mφ比TBH脾脏Mφ更能刺激自身反应性T细胞增殖。外源性IL-10或用IL-10预孵育的Mφ可将TBH Mφ刺激的自身反应性恢复到正常水平。IL-10处理对NH Mφ刺激的自身反应性几乎没有影响。在T细胞增殖试验中，IL-10抑制了TBH Mφ分泌抑制分子，因为来自IL-10预处理的TBH Mφ同基因NH T细胞培养物的上清液中抑制分子水平降低。当用抗IL-10单克隆抗体中和内源性IL-10活性时，NH或TBH Mφ刺激的自身反应性T细胞增殖略有但显著降低。虽然已知IL-10可抑制Mφ依赖的外来抗原呈递细胞的T细胞增殖，但本研究表明，IL-10通过抵消Mφ产生抑制分子来恢复肿瘤生长期间的自身反应性T细胞功能。这些数据表明，IL-10通过下调抑制性Mφ活性来上调抗癌自身反应性T细胞反应。
