Senescence and cytokines modulate the NK cell expression

We have been investigating senescence-related changes in human peripheral blood natural killer (NK2) cells. Data accumulated so far consistently and clearly show that both basal and cytokine (IL-2 and interferon alpha and gamma) induced antitumor MHC-unrestricted cytotoxic activity of NK cells are well-preserved in the healthy elderly. To investigate if the non-cytotoxic functions of NK cells are also spared from the influence of senescence, recombinant IL-2-inducible secretion of IFN-gamma, which serves as a first line of defense, was examined. The amount of IFN-gamma secreted by purified, 18 h activated NK cells from the elderly was only 25 percent of that released by the cells from the young. Thus, the type 1 cytokine-inducible cytotoxic and cytokine secretory functions appear to be dissociable properties of NK cells, at least in the elderly. However, this aging-related early phase secretory deficit could be overcome by chronic stimulation with IL-2 (7 day culture). Since different subsets could perform different functions, we analyzed the NK subsets by flow cytometry. A minor CD56bright subset and a major CD56dim subset could be distinguished based on the density of expression of the cell surface CD56 molecule (N-CAM). We inquired if immunosenescence is likely to impact the steady-state level of circulating NK subsets. A significant decrease (P < 0.01) in percent CD56bright among CD56+ cells was observed in the elderly with a relative sparing of the CD56dim subset. The CD56bright/CD56dim ratio, perhaps representing NK cell maturity status, declined with age. This maturation-related subset redistribution and partial loss during aging of high affinity IL-2 alpha beta gamma receptor bearing 'immature' CD56bright NK cells has not been reported before. It could be a consequence of the decline in the level of IL-2 during aging. It is concluded that post-adolescent age-associated modulations in human NK cells are not expressed uniformly; they are pronounced in some, subtle in others but negligible in yet other biological parameters.