Krishnaraj R
College of Medicine, University of Illinois, Chicago 60612.
Cell Immunol. 1992 Oct 1;144(1):11-21. doi: 10.1016/0008-8749(92)90221-a.
Aging is known to modulate the affinity and sensitivity of receptors for hormones and regulatory molecules. We have shown previously that exogenous adenosine triphosphate (ATP), perhaps acting as a purinoceptor agonist, can down-regulate the cell-mediated anti-tumor natural cytotoxic activity of human peripheral blood natural killer (NK) cells. We have extended these studies to investigate whether this effect is modulated during immunosenescence, and if so, whether it is gender-restricted or NK subset-associated. While the inhibitory effect is demonstrable in most individuals, there is a gender-restricted, age-associated transition in the sensitivity of NK cell activity to inhibition by ATP at 2.5 x 10(-5) to 80 x 10(-5) M in vitro. Data from both suboptimal (100 microM) and optimal (800 microM) inhibitory doses of ATP support this conclusion. The ID20ATP were 10.2 x 10(-5) and 17.8 x 10(-5) M for the young (less than 40 years) and elderly (greater than 70 years) females, respectively (P = 0.02). The frequency distribution curve of ATP sensitivity shifts to the left in the elderly, i.e., the sensitivity to be inhibited at 50% or more by ATP was expressed by one-half of young and one-fifth of elderly female donors. Linear regression analysis suggests an inverse relationship between percentage CD57+ and percentage CD16+57+ (but not percentage CD16+) NK subsets and sensitivity to down-regulation by ATP. The mean percentage of the above NK cell phenotypes among lymphocytes from young and old female donors differ significantly (less than 0.0001). The data suggest that the presence of CD57 antigen-positive cells may render NK cells relatively more resistant to the action of purinoceptor agonists such as ATP. Thus in females, immunosenescence results in a diminished ability of NK cells to transduce those signals that may normally mediate ATP-induced suppression of NK cytolytic activity. Such a diminished ability may be an immunobiological advantage to aging NK cells since they can be kept at a higher steady-state level of (anti-tumor cytotoxic) activity through a protection from negative modulators. These findings have an implication on the lower rate of mortality due to cancer seen in older women compared to that in older men. It is suggested that the ATP-NK cell interaction through the P2 purinoceptor may serve as a potentially useful model to study immunosenescence, ontogenic, or gender-specific changes in NK cells at the cell surface level.
已知衰老会调节激素和调节分子受体的亲和力和敏感性。我们之前已经表明，外源性三磷酸腺苷（ATP）可能作为嘌呤受体激动剂，可下调人外周血自然杀伤（NK）细胞的细胞介导抗肿瘤自然细胞毒性活性。我们扩展了这些研究，以调查这种效应在免疫衰老过程中是否受到调节，如果是，它是否受性别限制或与NK亚群相关。虽然在大多数个体中都能证明这种抑制作用，但在体外，当ATP浓度为2.5×10⁻⁵至80×10⁻⁵M时，NK细胞活性对ATP抑制的敏感性存在性别限制、与年龄相关的转变。来自次优（100 microM）和最优（800 microM）抑制剂量ATP的数据支持这一结论。年轻（小于40岁）和老年（大于70岁）女性的ATP ID20分别为10.2×10⁻⁵和17.8×10⁻⁵M（P = 0.02）。老年人中ATP敏感性的频率分布曲线向左移动，即，ATP抑制50%或更多时的敏感性在年轻女性供体的一半和老年女性供体的五分之一中表现出来。线性回归分析表明，CD57⁺百分比与CD16⁺57⁺（但不是CD16⁺）NK亚群百分比与对ATP下调的敏感性之间呈负相关。年轻和老年女性供体淋巴细胞中上述NK细胞表型的平均百分比差异显著（小于0.0001）。数据表明，CD57抗原阳性细胞的存在可能使NK细胞对嘌呤受体激动剂如ATP的作用相对更具抗性。因此，在女性中，免疫衰老导致NK细胞转导那些可能正常介导ATP诱导的NK细胞溶解活性抑制信号的能力减弱。这种减弱的能力可能是衰老NK细胞的一种免疫生物学优势，因为它们可以通过免受负调节因子的影响而保持在更高的（抗肿瘤细胞毒性）活性稳态水平。这些发现对老年女性与老年男性相比因癌症导致的较低死亡率具有启示意义。有人提出，通过P2嘌呤受体的ATP - NK细胞相互作用可能作为一个潜在有用的模型，用于在细胞表面水平研究NK细胞的免疫衰老、个体发生或性别特异性变化。
