Jewett A, Bonavida B
Department of Microbiology and Immunology, UCLA School of Medicine 90024.
Cell Immunol. 1993 Oct 15;151(2):257-69. doi: 10.1006/cimm.1993.1236.
Highly purified peripheral blood-derived NK cells can be separated into three functionally defined subpopulations, namely, non-target binding free cells, binders, and killers. The free cell subset is the least mature and was examined for its response to IL-2-mediated activation and the role of endogenous secretion of TNF-alpha in its maturation and differentiation. The findings demonstrate that endogenous TNF-alpha secretion is prerequisite for the initiation of IL-2-mediated activation of free cells into killer cells. The addition of IL-2 to free cells upregulated the surface expression of IL-2R (TAC), TNF-R (p75), CD69, and ICAM-1 antigens and also stimulated cell proliferation. Furthermore, the addition of IL-2 to free cells resulted in the induction of cytotoxic activity and stimulation of free cells to become binder and killer cells. All of these IL-2-mediated manifestations are shown to be downregulated by the addition of anti-TNF-alpha antibody. However, IL-2-mediated TNF-alpha secretion was not affected by the addition of anti-TNF-alpha antibody. The specificity of the anti-TNF-alpha antibody-mediated inhibition was corroborated by the failure of the antibody to inhibit interferon-alpha-mediated activation of free cells into killer cells. Most of the events associated with the inhibitory activity of anti-TNF-alpha antibody were mimicked by the addition of IL-4 to IL-2-treated free cells. These findings suggest that the IL-2-mediated maturation and differentiation of the immature free cells to become cytotoxic and proliferate are the result of a sequence of events that are initiated by the secretion of endogenous TNF-alpha.
高度纯化的外周血来源的自然杀伤细胞（NK细胞）可分为三个功能明确的亚群，即非靶标结合游离细胞、结合细胞和杀伤细胞。游离细胞亚群最不成熟，研究了其对白细胞介素-2（IL-2）介导的激活的反应以及内源性肿瘤坏死因子-α（TNF-α）分泌在其成熟和分化中的作用。研究结果表明，内源性TNF-α分泌是IL-2介导的游离细胞激活为杀伤细胞起始的先决条件。向游离细胞中添加IL-2可上调IL-2受体（TAC）、TNF受体（p75）、CD69和细胞间黏附分子-1（ICAM-1）抗原的表面表达，并刺激细胞增殖。此外，向游离细胞中添加IL-2导致细胞毒性活性的诱导以及游离细胞被刺激成为结合细胞和杀伤细胞。所有这些IL-2介导的表现均显示通过添加抗TNF-α抗体而下调。然而，IL-2介导的TNF-α分泌不受添加抗TNF-α抗体的影响。抗TNF-α抗体介导的抑制作用的特异性通过该抗体未能抑制干扰素-α介导的游离细胞激活为杀伤细胞得到证实。向用IL-2处理的游离细胞中添加IL-4模拟了与抗TNF-α抗体抑制活性相关的大多数事件。这些发现表明，IL-2介导的未成熟游离细胞成熟和分化为具有细胞毒性并增殖是由内源性TNF-α分泌引发的一系列事件的结果。
