CORD-BLOOD CD16(-) CELLS WITH LOW LYTIC ACTIVITY ARE POSSIBLE PRECURSORS OF MATURE NATURAL-KILLER-CELLS()56()

Human natural killer (NK) cells are defined as being membrane CD3(-), CD16(+), and/or CD56(+) lymphocytes; however, little is known about th e ontogenic development and maturational pathways of human NK cells. T he functional, phenotypic, and maturational characteristics of human u mbilical cord blood (CB) NK cell subsets were studied to gain insight into the ontogenic and maturational pathways of human NK cells. We hav e previously shown that there is a novel subset of CD16(+) CD56(-) NK cells present in CB. Here we further demonstrate differences in the ex pression of the NK-associated molecules CD2, CD7, CD8, and CD25 betwee n CB and peripheral blood (PB) NK cells and between CB NK cell subsets . Although CB NK cell subsets were deficient in or had less lytic acti vity against K562 cells compared to PB NK cells, CB NK cells did posse ss the lytic molecules perforin and granzyme B and when artificially s timulated to secrete their granules during lytic assays, were capable of lytic activity equivalent to that of PB NK cells. Regardless of dif ferences in phenotype and function of CB NK cell subsets, short-term a nd long-term incubation with cytokines induced functional (adult-like NK activity) and phenotypic (adult-like CD16(+)56(+) or CD16(-)56(+) s urface antigen phenotype) maturation, respectively. Interleukin-2 (IL- 2), IL-12, and IL-15, but not IL-7, interferon-gamma (IFN-gamma) nor t umor necrosis factor-alpha (TNF-alpha) induced functional and phenotyp ic maturation of CB NK cell subsets. Interestingly, culture of CB NK c ell subsets with IL-2 or IL-15 led to acquisition of predominantly a C D16(+)56(+) phenotype, while culture with IL-12 led to acquisition of both CD16(+)56(+) and CD16(-)56(+) phenotypes. Both functional and phe notypic maturation were not dependent upon proliferation. Studies usin g neutralizing anti-IFN-gamma and anti-TNF-alpha antibodies showed tha t survival and phenotypic maturation upon cytokine stimulation is infl uenced by endogenous production of TNF-alpha but not IFN-gamma. These results demonstrate that CB NK cell subsets are functionally and pheno typically immature but are capable of maturation. Additionally, CD16()56(-) NK cells are implicated as possible precursors of mature CD16()56(+) and CD16(-)56(+) NK cells. (C) 1997 Academic Press.