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Natural Killer Cells and Their Relationship to T-Cells: Hypothesis

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Natural Killer Cells and Their Relationship to T-Cells: Hypothesis (CANCER RESEARCH 46, 2651-2658, June 1986) Perspectives in Cancer Research Natural Killer Cells and Their Relationship to T-Cells: Hypothesis on the Role of T-Cell Receptor Gene Rearrangement on the Course of Adaptive Differentiation Zvi Grossman and Ronald B. Herberman' TelAviv University, TelAviv, JsraeIfZ. G.J,and Pittsburgh Cancerinstitute andDeparrments ofMedicinefR. B. HjandMathematics[Z. G.J, University of Pittsburgh, Pittsburgh, Pennsylvania 15213 Natural killer cells were discovered about 13 years ago during has concerned the lineage of NK cells and their possible rela studies of cell-mediated cytotoxicity against tumor cells (see tionship to the T-cell or macrophage lineages. Three major Ref. 1 for review). Although investigators in this area of re alternatives havebeenextensively considered: (a) NK cells may search expected to find specific cytotoxic activity of tumor be derived from, and closely associated with, the myelomono bearing individuals against autologous tumor cells or against cytic lineage, and most closely related to macrophages; (b) NK allogeneic tumors of similar or the same histological type, cells may be related to the T-cell lineage; (c) NK cells may appreciable cytotoxic activity was also observed with lympho represent a separate lineage derived from bone marrow stem cytes of normal individuals. It soon became clear that such cells and they simply may share some cell surface and other cytotoxic activity was mediated by a particular subpopulation characteristics with cells from other bone marrow-derived lin of effector cells, which have come to be known as NK cells.2 eages. NK cells may be defined as effector cells with spontaneous Most of the experimental evidence for an association of NK cytotoxic reactivity against a variety of target cells, particularly cells with macrophages has been relatively weak and could be tumor cells, tumor cell lines, and a limited variety of normal otherwise accounted for. The expression of 0KM! or Mac I cells (e.g., virus-infected fibroblasts and subpopulations of bone on NK cells was initially taken as indicative of an association marrow cells and thymus cells). The characteristics of NK cells with macrophages (1 1, 12), but recent evidence has indicated and their possible relationship to T-cells or macrophages have that these antigens are on the cell surface receptor for C3bi and been studied extensively (see Ref. 2 for review). NK cells have are not restricted to macrophages(13), being expressedalso on been clearly distinguished from typical macrophages, being a subsetof T-cells which appear unrelated to NK cells. A study nonphagocytic and mostly nonadherent and lacking some cell with mouse bone marrow cells indicated that NK activity de surface markers which are characteristic of most if not all veloped from a population enriched in macrophage precursors monocytes and macrophages. Similarly, NK cells have been (14). However, the population containing the NK precursors distinguished from CTL since their cytotoxic reactivity has not was not a pure population of macrophagesand could have also been found to be restricted by the MHC, with some of the most contained nonmacrophage precursors for NK cells. Along the sensitive targets for NK activity lacking detectable MHC anti samelines, Roder et a!. (15) reported that a population of cells gens, and NK cells have been shown to lack cell surface markers highly enriched in NK activity could undergo an oxidative burst which are characteristic of CTL (e.g., Lyt-2 in the mouse). One and this evidence was taken as definitive evidence for an asso ofthe most consistent features of NK cells, which has permitted ciation of NK cells with macrophages (16). However, subse their purification and detailed comparison with other types of quent studies indicated that the generation of the oxidative effector cells, is their close association with a morphological burst was dependent on the interaction of a small number of subpopulation of cells, the LGL (3). contaminating macrophages with the NK cell population (17). Over the past several years, much of the attention devoted to Another indication for the lack of an association of NK cells NK cells has concerned their possible in vivo relevance, partic with macrophages has come from studies of the expression of ularly with regard to their possible roles in host defense against receptors for colony-stimulating factor 1which havebeenfound to be expressed on most cells in the macrophage lineage. These tumor growth (4). Some evidence has been accumulated to receptors could not be detected on a purified population of rat indicate a possible role of NK cells in immunosurveillance NK cells.3 against certain types of tumors. More extensive and convincing The possible relationship of NK cells with the T-cell lineage evidence has been accumulated to indicate an important role of has been considerably more difficult to evaluate. On the one NK cells in resistance to progressive growth and metastasis of hand, it has been clear that NK cells are different from mature tumors (see Refs. 5 and 6 for recent reviews ofthis information). or classical T-cells. High levels of NK activity have been found There has also been much recent interest in elucidating the in nude athymic or neonatally thymectomized mice and rats mechanism of cytotoxicity by NK cells (see Refs. 7 and 8 for (18, 19). Characteristicmarkers of T-cells, suchas Lyt-2 for reviews). A potent cytolytic protein, termed cytolysin, has been mousecells(20) or T3 or TiOl for humancells(21), havebeen isolated from the granules of LGL (9) and this granule cytolysin undetectable on NK cells. In addition, recent studies have appears to be intimately involved in the mechanism of cytotox indicated that there is a lack of a productive rearrangement of icity by NK cells. In addition, NK cells have been shown to T-cell receptor genes in rat LGL leukemias (22) or in normal release a soluble NK cytotoxic factor which might be an alter LGLof variousspecies(23).@ native but less efficient mechanism of lysis (10). Despite such negative evidence, there have been numerous One of the most controversial areas of research on NK cells 3 T. Barlozzari, C. W. Reynolds, R. Stanley, and R. B. Herberman, manuscript Received 1/21/86; accepted 2/20/86. in preparation. I To whom requests for reprints should be addressed. 4 H. A. Young, J. R. Ortaldo, R. B. Herberman, and C. W. Reynolds. Analysis 2 The abbreviations used are: NK cells, natural killer cells; CTL, cytotoxic T of T cell receptors in highly purified human and rat large granular lymphocytes lymphocyte(s); MHC, major histocompatibility complex; LGL, large granular (LGL): lack of functional 1.3 kb fl-chain mRNA, J. Immunol., 136: 2701—2704, lymphocyte(s); lL-2, interleukin 2. !986. 2651 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 1986 American Association for Cancer Research. ADAPTIVE DIFFERENTIATION OF NK CELLS AND T-CELLS suggestionsfor some relationship of NK cells to T-cells: have been generated with regard to the possible relationship of I . NK cells have been found to express some T-cell-associated NK cells and T-cells, which often seem rather contradictory or markers. The majority of human NK cells express low-affinity divergent, it seems quite important to reassessthe data and to receptors for sheeperythrocytes (24) and react with monoclonal provide a theoretical framework to accommodate most if not antibodies against these receptors (21). A subset of human NK all of the available information. As an early hypothesis on the cells also expressesthe T8 antigen, a characteristic marker for association between NK cells and T-cells, it was suggested, the cytotoxic-suppressor subsetof human T-cells (2 1) and most based on the data showing high levels of NK activity in nude rat NK cells express the analogous OX8 marker (25). or neonatally thymectomized mice, that NK cells might repre 2. NK cells as well as T-cells respond to IL-2, with stimulation sent a stage of prethymic T-cells, which accumulate when the of cytotoxic activity and also proliferation (26—28).The IL-2- ability to further differentiate into mature T-cells is blocked by dependent growth of NK cells has been found to depend on the absence of the thymus (39). Another hypothesis, along the expression of IL-2 receptors which are antigenically the same same line, suggested that NK cells represented an early stage as on activated T-cells (28). However, stimulation of cytotox in the development of T-cells and that both effector cell types icity of human NK cells appears to be independent of the Tac shared similar receptors (40). Subsequently, Klein (41) noted IL-2 receptor (28). that NK-like activity develops in alloantigen-stimulated cultures 3. The majority of human T@yleukemias have been found to prior to the development of CTL activity and suggested that have most of the characteristics of LGL, express characteristic NK activity represents a polyclonal response of T-cells during T-cell markers, often have NK activity (29), and have rearrange early stagesofactivation and prior to the development of MHC ments of the gene for the /3-chain of the T-cell receptor (23). restricted reactivity to specific antigens. Several years ago, we 4. NK cells and CTL appear to share similar if not identical also proposed a hypothesis on the origin and specificity of NK lytic mechanisms. The characteristics of the cytolysin isolated cells (42). This hypothesis offered an interpretation of the from the granules of LGL (9) are virtually identical to those similarities and differences between NK cells and CTL and was described for the polyperforin of CTL (30). In contrast, cyto basedon the assumption ofa common T-cell lineage but distinct toxic macrophages do not appear to have an analogous granule specificity repertoires.
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