On the heterogeneity of murine natural killer cells.

Abstract

The heterogeneity of cells capable of exerting spontaneous cytotoxicity in vitro was studied using antisera to several genetically determined surface markers on mouse lymphocytes. Four phenotypes of cells derived from fresh or cultured murine lymphoid tissue had natural killer (NK) activity in vitro. On effector cell subset, termined NKI cells, had the serological phenotype of Thy-1-, Lyt-2-, Qa-5+, and lysed measles virus persistently infected target [HeLa (human cervical carcinoma)] cells (HeLa-Ms) but not P815 mouse mastocytoma cells. It corresponds with the NK cells described in most systems in which lymphoma targets are commonly used. A 2nd subset, with the same target cell specificity, termed NKT is a thymus-independent cell with the phenotype Thy-1+, Lyt-2-, Qa-5+, Ly-5+. A 3rd subset of NK cells, termed T killer (TK) cells, deriving from cultures of conventional but not nude mouse spleens, mediated spontaneous cytotoxicity of P815 mastocytoma cells, but not of virus-infected targets. It has a phenotype of Thy-1+, Lyt-2+, Qa-5-, Ly-5+, apparently identical with that of conventional, antigen-specific cytotoxic T lymphocytes. The 4th phenotype of NK cells, termed NKM derived primarily from cultures of bone marrow, is cytotoxic for HeLa-Ms but not p815 and expresses only Ly-5+ among the various markers tested. Beige mice possess normal TK and NKM activities, but were deficient in NKI and NKT activity. Nude mice lacked TK cells, but had normal NKI, NKT and NKM activity. All NK cell subsets express the Ly-5 surface marker. The existence of 4 phenotypically distinct NK effector cells was strengthened by studies on selective regulation of their activity by 2 different biological factors. Interferon (IFN) augmented NK activity of only NKI cells; the activity of IFN on NKT cells could not be directly tested, but IFN was without positive effect on TK on NKM cells. Partially purified IFN-free interleukin 2 (IL-2) augmented the activities of both the TK and NKT subsets, but not of NKI or NKM cell. IL-2 was active in agumentig NK activity in spleen cells obtained from both conventional and nu/nu mice, but was without effect on spleens of nu/nu mice depleted of Thy-1+ cells. IL-2 apparently acts primarily, if not exclusively, on Thy-1- cells. Natural cytotoxicity in vitro can apparently be mediated by several distinct cell populations under different gentic and regulatory control. The cell lineages of each subset should be defined and delineated and the role of the independent subsets in resistance to virus infections and tumors should be assessed.