Differential responses to interleukin 2 define functionally distinct subsets of human natural killer cells

Human natural killer (NK) cells can be subdivided into two populations based on the density of cell surface CD56 antigen. The great majority (approximately 90%) of NK cells express CD56 at low levels (the CD56dim phenotype), whereas a small NK cell subset (approximately 10%) exhibits approximately fivefold greater density of surface CD56. Exposure to exogenous interleukin 2 (IL 2) induces tenfold greater proliferation of CD56bright cells compared to CD56dim lymphocytes, even though both subsets constitutively express similar levels of intermediate affinity IL 2 receptor (IL 2R) p75 chains. Incubation with IL 2 alone or irradiated target cells alone could induce expression of the IL 2R p55 chain by both CD56bright and CD56dim NK cells; a combination of both stimuli was most effective. IL 2R p55 induction was evident after co-culture of NK cells with both NK-sensitive and NK-resistant cell lines or with antibody-coated target cells. Activation of NK cells with IL 2 plus target cells resulted in enhanced proliferation compared to activation with IL 2 alone; target cells alone did not induce significant proliferation. Although both NK cell subsets appeared to express high-affinity IL 2R p75/p55 heterodimers after stimulation with target cells and IL 2, proliferation of CD56dim cells remained minimal after such activation; activated CD56dim cells consistently demonstrated less proliferation to IL 2 than did resting CD56bright cells. In contrast, CD56bright NK cells exhibited even greater proliferation after stimulation with target cells. Almost all CD56dim NK cells expressed CD16 (Fc gamma R III) as well as the NK zeta chain, whereas less than 50% of CD56bright cells express either CD16 or zeta. CD56bright and CD56dim lymphocytes, thus, appear to represent distinct subpopulations of NK cells with different functional activities. Unlike CD56bright cells, CD56dim NK cells do not proliferate optimally to IL 2, even after the latter have been stimulated to express both IL 2R p55 and IL 2R p75. Efficient proliferation of CD56dim NK cells may, thus, require additional or alternative signals.