Blay J Y, Bertoglio J, Fradelizi D, Chouaib S
Laboratoire d'Immunologie, UA 1156 CNRS, Institut Gustave Roussy, Villejuif, France.
Int J Cancer. 1989 Oct 15;44(4):598-604. doi: 10.1002/ijc.2910440407.
We have previously reported on the synergistic effect of IL2 and TNF on the differentiation of LGL into LAK effectors. In the present study, we have further investigated the molecular basis of this synergistic mechanism and examined the role of TNF in the induction of LAK activity. We show that the generation of optimal LAK activity by low doses of IL-2 in the presence of TNF involves the induction of high-affinity IL2 receptors on LGL and occurs without promoting significant proliferation, suggesting a functional activation rather than a proliferative expansion of LAK precursors. Using blocking studies with anti-Tac and with an anti-IL2 (IHII), which specifically inhibits the binding of IL2 to the p75 IL2 receptor component, we also show that both the p55 and the p75 are involved in the increase in TNF binding sites on LGL and the subsequent acquisition of LAK activity. We also demonstrate that the failure of low doses of IL2 to induce LAK activity is related to their incapacity to induce TNF production. Moreover, when specific antibodies against TNF were added to the culture, the differentiation of LGL into LAK effectors by optimal concentrations of IL2 in our system (2.5-5.0 ng/ml) was partially inhibited. This suggests that TNF may be a physiologic mediator in the sequential activation stages of LGL into LAK effectors.
我们之前曾报道过白细胞介素2（IL2）和肿瘤坏死因子（TNF）对大颗粒淋巴细胞（LGL）分化为淋巴因子激活的杀伤细胞（LAK）效应细胞的协同作用。在本研究中，我们进一步探究了这种协同机制的分子基础，并考察了TNF在LAK活性诱导中的作用。我们发现，在TNF存在的情况下，低剂量IL-2产生最佳LAK活性涉及诱导LGL上的高亲和力IL2受体，且在不促进显著增殖的情况下发生，这表明是LAK前体细胞的功能激活而非增殖性扩增。使用抗Tac抗体和抗IL2抗体（IHII）进行阻断研究，后者特异性抑制IL2与p75 IL2受体成分的结合，我们还表明p55和p75均参与LGL上TNF结合位点的增加以及随后LAK活性的获得。我们还证明，低剂量IL2未能诱导LAK活性与其无法诱导TNF产生有关。此外，当向培养物中添加抗TNF特异性抗体时，在我们的系统中（2.5 - 5.0 ng/ml），最佳浓度的IL2诱导LGL分化为LAK效应细胞的过程受到部分抑制。这表明TNF可能是LGL向LAK效应细胞顺序激活阶段的生理介质。
