Natural killer cells wear different hats: effector cells of innate resistance and regulatory cells of adaptive immunity and of hematopoiesis Giorgio Trinchieri Natural killer (NK) cells were originally defined by their ability to lyse tumor cells or virus-infected cells and identified as one type of effector cells of the non-antigen specific innate resistance. However, many recent studies have widened the interpretation of the role of NK cells in immunity and shown that NK cells have important regulatory roles in innate resistance, antigen-specific adaptive immunity, and, possibly, in hematopoiesis. These functions of NK cells more than on their cytotoxic activity, are probably dependent on their ability to produce lymphokines, particularly interferon- γ (IFN- γ). NK cells are important for antigen-independent activation of phagocytic cells early in infection and for favoring the development of antigen-specific T helper cells type I, producing IFN- γ and IL-2. A role for NK cells in suppression of hematopoiesis and in induction of septic shock may represent a pathological exaggeration of the physiologic functions of NK cells in innate resistance. Key words: natural killer cells / interferon- γ / macrophage activation / hematopoiesis / T-helper cells NK CELLS ARE LYMPHOCYTES characterized by their ability to lyse tumor-derived, virus-infected, and cer- tain normal target cells in the absence of previous sensitization or activation. 1 The in-vivo functions of NK cells are not completely understood. They have a role in defense against virus infection and against metastatic diffusion of tumors, but they may also have important regulatory effects on both adaptive and non-adaptive immune responses and on hematopoie- sis. 1 Although resting mature NK cells are cytotoxic, their activity is increased by different cytokines, including interferons and IL-2. 2,3 The cytolytic activity of NK cells, by which they were originally discovered and defined, may not represent the most important in-vivo function of these cells. Indeed NK cells are also powerful producers of lymphokines such as IFN- γ, TNF, GM-CSF, IL-3, M-CSF and others. 3-5 In-vivo NK cells are particularly important as producers of cytokines, mainly IFN- γ, early during infections or immune responses to antigens because, unlike most T cells, they do not require prestimulation, but rapidly respond to various stimuli. 3 T cells are induced to produce cytokines primarily by antigen stimulation in the presence of co-stimulatory factors. Thus, only the minor subset of T cells expressing the clonally distributed T-cell receptor recognizing the specific antigens are efficiently stimulated, and often an expansion of the antigen-specific T cell clones for several days in vivo during an immune response may be required, especially in primary response, before T cells become efficient producers of IFN- γ production. In the case of NK cells, cytokine production is induced by non-specific stimuli (immune complexes and surface structures of target cells and, possibly, of infectious microorganisms) which are able to activate most NK cells. Other cytokines, produced by accessory cells or T cells, such as IL-12, IL-2, TNF and IL-1, often acting in synergy, also induce NK cells to produce IFN- γ and other lymphokines. 3,5,6 Although these cyto- kines are also effective inducers of IFN- γ production in T cells, NK cells are more prompt and efficient producers, 3 because, unlike T cells, they constitutively express low levels of the IL-2 receptor  chain and, possibly, one of the chains of the receptor for IL- 12. 7-9 NK cells have a key role in antigen independent phagocytic cell activation The ability of NK cells to produce cytokines with potent activatory effect on phagocytic cells has led to the postulate of a role for this cell type in inflamma- tion during infection. 1,4 The original in-vivo observa- tion that NK cells by producing IFN- γ and other cytokines may have a central role in the antigen and From the The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA seminars in IMMUNOLOGY, Vol 7, 1995: pp 83–88 ©1995 Academic Press Ltd 1044-5323/ 95/ 020083 +06$8.00/ 0 83