Proliferative responses of circulating human NK cells: delineation of a unique pathway involving both direct and helper signals

The present studies were performed to investigate mechanisms of human natural killer (NK) cell activation. NK-active cells were purified out of heterogeneous large granular lymphocytes (LGL)-enriched suspensions using a “pan NK”-specific monoclonal antibody termed anti-NKHlA. It was found that treatment of NKHlA+-sorted cells by T lymphocyte mitogens such as phytohemagglutinin (PHA) or anti-TH2 plus anti-Tll3 did not induce proliferative responses. In fact, there was no measurable interleukin 2 (IL 2) secretion and no significant increase in IL 2 susceptibility following incubation with either PHA or anti-TH2 plus anti-T113. However, as opposed to small resting T lymphocytes, NKH1A+ cells moderately proliferated in the presence of IL2. This IL 2-dependent proliferation was dramatically increased after interaction between NK-active lymphocytes and certain hematopoietic cell lines such as K562 or EBV-transformed lymphoblastoid cell lines. These studies indicate that unique activation mechanisms can be identified when NK lymphocytes are purified out of LGL-enriched fractions. The NK activation pathway delineated here appears essentially distinct from those described for T lymphocytes. Indeed the nature of the NK cell/inducing cell interaction is unknown and triggering cannot be related, for example, to a conventional allogeneic effect mediated through membrane exposure of class I or class II major histocompatibility complex gene products. Moreover, these interactions do not lead to the development of autocrine responses. Together the present results support the view that direct signals can preac-tivate NK cells but are not sufficient to trigger proliferation which must therefore be regulated by helper populations.