Offner H, Thieme T, Vandenbark A A
Immunology Research Laboratory, Veterans Administration Medical Center, Portland, OR 97201.
J Immunol. 1987 Nov 15;139(10):3295-305.
The cluster designation (CD)4 molecule is one of several nonpolymorphic T lymphocyte surface proteins that have been implicated in T cell-target cell interactions, and is thought to play an important role in regulating T helper cell function. Previously, we found that gangliosides inhibited the function of rat T helper cell lines, and simultaneously inhibited the expression of the rat CD4 molecule identified by the W3/25 antibody. We have now evaluated the generality and mechanism(s) of ganglioside-induced modulation of CD4 expressed by mouse, rat, and human T helper lymphocytes. Ganglioside pretreatment induced rapid and selective disappearance of the CD4 molecule from T helper cells of all three species. The ganglioside effect was temperature- and dose-dependent, reversible within 24 hr of ganglioside removal, azide-insensitive, and was neutralized completely by 10% serum. CD4 modulation appeared to be a general property of gangliosides since the effect could be induced similarly by highly purified individual gangliosides with varying amounts of sialic acid, or by mixed gangliosides. The activity of gangliosides appeared to require both the lipid and sialated oligosaccharide moieties. Gangliosides did not inactivate antibody function, but prevented binding at the cell surface by 12 different monoclonal antibodies specific for a variety of different CD4 epitopes. Preclearance of CD4 by antibody-mediated capping reduced binding of 3H-GM1 to T helper cells. Labeled GM1 bound to several detergent-extracted and transblotted lymphocyte-associated proteins, but apparently did not bind directly to the CD4 molecule under these conditions. These results indicate that gangliosides induce a profound change in the molecular orientation of CD4 within the T helper cell membrane which renders epitopes on the CD4 molecule inaccessible to antibody. This ganglioside effect represents a novel pathway which may contribute to the understanding of the role of CD4 as a regulatory molecule and as a specific receptor for the acquired immune deficiency syndrome virus.
簇分化抗原（CD）4分子是几种参与T细胞与靶细胞相互作用的非多态性T淋巴细胞表面蛋白之一，被认为在调节辅助性T细胞功能中起重要作用。此前，我们发现神经节苷脂可抑制大鼠辅助性T细胞系的功能，同时抑制由W3/25抗体识别的大鼠CD4分子的表达。我们现在评估了神经节苷脂诱导的对小鼠、大鼠和人类辅助性T淋巴细胞表达的CD4的调节作用的普遍性及其机制。神经节苷脂预处理导致所有这三个物种的辅助性T细胞上的CD4分子迅速且选择性地消失。神经节苷脂的作用是温度和剂量依赖性的，在去除神经节苷脂后24小时内可逆，对叠氮化物不敏感，并且可被10%血清完全中和。CD4调节似乎是神经节苷脂的一个普遍特性，因为高度纯化的含有不同唾液酸量的单个神经节苷脂或混合神经节苷脂都能类似地诱导这种效应。神经节苷脂的活性似乎需要脂质和唾液酸化寡糖部分。神经节苷脂不会使抗体功能失活，但会阻止12种针对多种不同CD4表位的不同单克隆抗体在细胞表面的结合。抗体介导的封帽作用对CD4的预先清除减少了3H-GM1与辅助性T细胞的结合。标记的GM1与几种经去污剂提取和转印的淋巴细胞相关蛋白结合，但在这些条件下显然不直接与CD4分子结合。这些结果表明，神经节苷脂诱导辅助性T细胞膜内CD4分子的分子取向发生深刻变化，使CD4分子上的表位无法被抗体识别。这种神经节苷脂效应代表了一条新途径，可能有助于理解CD4作为调节分子以及作为获得性免疫缺陷综合征病毒特异性受体的作用。
