Negative modulation of human NK cell activity by purinoceptors. 2. Age-associated, gender-specific partial loss of sensitivity to ATP.

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.