The mononuclear cell in human blood which mediates antibody-dependent cellular cytotoxicity to virus-infected target cells. II. Identification as a K cell.

Studies were carried out to determine whether the mononuclear cell in human blood which mediates antibody-dependent cellular cytotoxicity (ADCC) to herpes simplex virus (HSV)-infected target cells has surface Fc receptors which participate in the reaction. The F (ab')2 fragment of human IgG antibody was inactive both in ADCC and in complement-mediated cytolysis, but retained the capacity to neutralize infectious virus, to agglutinate erythrocytes coated with viral antigens, and to bind to the surface of virus-infected cells. Treatment of sensitized virus-infected target cells with staphylococcus protein A, which has affinity for the Fc epitope of IgG, strongly reduced their susceptibility to lysis by ADCC in a dose-dependent relationship. These findings indicate that the Fc portion of IgG antibody to the virus is necessary for cytotoxicity. Treatment of blood mononuclear cells with either heat-aggregated gamma-globulin or HSV immune complexes inhibited effector cell activity. The presence of "third party" cellular immune complexes also strongly inhibited ADCC. Adsorption of mononuclear cells to plastic surfaces coated with soluble third party immune complexes resulted in a significant reduction in effector cell activity. These findings demonstrate that the ADCC effector cell possesses surface Fc receptors which are utilized in the ADCC reaction. The presence of Fc receptors on the surface of the effector cell indicates that it is a K cell rather than a null cell.     

Characterization of IL-2-induced murine cells which exhibit ADCC activity

The incubation of murine splenocytes in recombinant interleukin 2 (IL-2) gives rise to both lymphokine-activated killer (LAK) cells capable of lysing fresh tumor cells and cells capable of mediating antibody-dependent cellular cytotoxicity (ADCC) in the presence of anti-H2 allosera. A similarity between these two IL-2-induced cell populations was found. The precursors of the cells mediating these activities were shown to be ASGM1 positive, Thy 1 negative, and radiosensitive. Cells taken from the spleen, thymus, and bone marrow were able to mediate ADCC after culture in IL-2. The effector cell was either Thy 1 positive or negative and was less affected by anti-Thy 1 plus C' treatment than cells which mediated LAK activity. In addition ADCC was exhibited in IL-2-cultured splenocytes from various murine strains and correlated with their LAK activity with one exception. While IL-2-cultured C57BL/6 splenocytes exhibited LAK activity similar to that of C3H LAK cells, no ADCC activity could be demonstrated in C57BL/6 cells. Study of the difference in the ability of these two strains to mediate ADCC revealed that IL-2-induced FcR+ cells in C3H thymocytes, but not in C57BL/6 thymocytes. Based on FACS analysis and on the radiosensitivity of the induction of both FcR+ cells and ADCC, it was suggested that IL-2 was expanding a small FcR+ cell population rather than inducing an increase in FcR density on the cell surface. The relationship between the IL-2-induced ADCC mediator and other IL-2-induced cells, as well as ADCC effector cells, and the possible implications of the results for the in vivo therapy of cancer based on ADCC are discussed.     

Multiple occurrence of spontaneous AKR/J lymphomas with T and B cell characteristics.

Three Thy 1.1-positive and surface IgM-positive (Thy 1+, SIg+) AKR/J lymphoma lines are described. These doubly marked tumors arose spontaneously in the peripheral lymphoid organs of 14- to 16-month-old AKR/J mice that either had spontaneous thymus atrophy or had been thymectomized at 1 month of age. All lines bore surface Thy 1.1, Ly,Ig(micron-chain) and Fc receptor (FcR), detectable by immunofluorescence. Immune response region (Iak) antigen was present on the two lines tested. Persistence of Thy 1.1 antigen and SIg after long-term tissue culture provided evidence that these markers were not passively acquired. One of these tumor lines, AkTB-1 always grows in lymph nodes as Thy 1.1-positive,SIg-negative tumors cells, whereas tumor cells growing in the spleen are initially Thy 1.1 positive, SIg negative, but they rapidly acquire SIg, FcR, and 1a between 18 and 21 days of passage.     

Migration and differentiation of bone marrow lymphocytes: development of surface immunoglobulin, Fc receptor, complement receptor, and functional responsiveness as studied with anti-allotype serum

Immunofluorescent studies using fluorescein isothiocyanate-conjugated mouse anti-allotype antibody were carried out to study the migration pattern and the development of surface Ig (SIg), Fc receptor for IgG (FcR gamma), and complement receptor (CR) or mouse bone marrow lymphocytes following intravenous injection into congenic mice. After transfer of bone marrow cells from CSW mice into untreated congenic CWB mice, the absolute number of donor-type SIg-bearing (SIg+) cells and the proportion of either FcR gamma- or CR-bearing (FcR gamma+ or CR+) cells in donor-type SIg+ cells were evaluated in the recipient spleen and the results were compared with those obtained after the transfer of CSW spleen cells. After injection of donor bone marrow cells, detectable donor-type SIg+ cells, although few initially, increased from day 1 to Day 2 and reached a plateau thereafter. The proportion of FcR gamma+ cells in donor-type SIg+ cells, although very low in the donor marrow inoculum, increased progressively after 1 day to reach a maximum at Day 5 (90%). On the other hand, following the transfer of spleen cells, the proportion of FcR gamma+ cells remained at high levels (90%) for 5 days after transfer. Likewise, the proportion of CR+ cells in donor-type SIg+ cells was very low (less than 1%) in the original donor bone marrow cells but high (60%) in the donor spleen cells. However, in transferring bone marrow cells this proportion also increased in the recipient spleen to reach a maximum (49%) at Day 5 although it was lower compared to the percentage of FcR gamma+ cells in donor SIg+ cells. Furthermore, the ability of functional responsiveness to antigen was also examined in the same system by detecting plaque-forming cells (PFC) from donor origin. In transferring donor bone marrow cells into recipient, the participation of donor cells in the PFC response was very low when the recipients were primed with sheep red blood cells at Day 3 after transfer. However, when the recipients were primed at Days 7 to 21 after transfer, increasing numbers of the donor marrow-derived cells were involved in the PFC response. Thus, the present study demonstrates that the bone marrow-derived lymphocytes, albeit lacking both distinctive surface receptors (IgM, FcR gamma, CR) and the functional responsiveness to antigen, continue their development along the B-cell lineage after migrating into the spleen, as evidenced by the surface receptor expression and participation in the antibody response.     

Studies of complement receptors on cytotoxic effector cells in human peripheral blood

The question of whether cells bearing complement receptors (CR) mediate cytotoxicity in vitro against allogeneic Chang liver cell targets was investigated by assessing peripheral blood mononuclear cells (PBMC) from normal humans for cell surface characteristics and cytotoxic capacity before and after depletion of CR+ cells capable of forming rosettes with sheep erythrocytes coated with 19S antibody and mouse complement (EAC) and depletion of Fc receptor-bearing cells capable of forming rosettes with human O+ erythrocytes coated with Ripley antibody (EA-Ripley). PBMC depleted of CR+ cells by density centrifugation contained markedly reduced proportions of phagocytes and sIg + cells and increased proportions of both sIg ?, FcR+ cells as well as cells forming rosettes with sheep erythrocytes (E). PBMC depleted of CR+ cells mediated cytotoxicity to an extent equal to or greater than that mediated by unfractionated PBMC in assays of spontaneous cell-mediated cytotoxicity (SCMC), antibody-dependent cellular cytotoxicity (ADCC), and mitogen-induced cellular cytotoxicity (MICC). Cells harvested from the EAC-rosette enriched pellet mediated cytotoxicity 5- to 10-fold less than unfractionated PBMC; however, the cytotoxic activity of the pellet could not be attributed to CR + effector cells since similar cytotoxic activity was present in cell pellets obtained by density centrifugation of PBMC which had been incubated with E coated with 19S antibody or E alone. PBMC depleted of EA-Ripley rosette-forming cells contained decreased proportions of sIg?, FcR+ cells and increased proportions of CR+ cells; PBMC so depleted contained virtually no SCMC and ADCC effector cell activity. These findings indicate that at least the majority of effector cells which mediate SCMC, ADCC, and MICC do not bear CR.     

Down-regulation of surface FcRI and decrease in antibody-dependent cellular cytotoxicity of cultured monocytes. Reversal by monensin or cytochalasin-D

To investigate the mechanisms involved in regulation of antibody-dependent cellular cytotoxicity (ADCC) mediated by human monocytes, 51Cr-labeled sheep red blood cells (RBC) were used as target cells in vitro. Monocytes incubated overnight at 37 degrees C before addition of SRBC and antibody exhibited a significant decrease in ADCC activity compared with freshly isolated cells. This pattern was observed with monocytes from all donors tested, regardless of the media used for culture. Supernatants from monocyte cultures did not inhibit the cytotoxic ability of fresh monocytes and cycloheximide, a protein synthesis inhibitor, could not reverse ADCC suppression in cultured monocytes, indicating that the alteration in ADCC is probably not due to inhibitory molecules secreted or synthesized during incubation. A correlation between the decrease in the number of surface FcRI and loss in ADCC ability of cultured monocytes was found. One mechanism for the reduced FcRI expression of 1-day-old monocytes may be rapid internalization that exceeds the rate of reexpression, because cytochalasin-D or monensin, each of which inhibits receptor internalization, maintained FcR expression as well as ADCC ability of cultured monocytes. These data illustrate mechanisms whereby alteration in the number of receptors may underlie loss of receptor-mediated functions, or be involved in augmentation of their biologic activity. The findings that important monocyte functions change under conditions of storage or culture have relevance to in vitro testing of various immune functions of monocytes performed clinically to monitor or guide therapy.     

Potentiation of cell-mediated lysis of xenogemeic tumor cells: the role of antiserum and effector cells.

The development of the immune response to xenogeneic tumor cells and the mechanism of potentiation of cell-mediated cytotoxicity (CMC) by xenoantiserum were investigated. The kinetics of potentiation of CMC resembled, both qualitatively and quantitatively, the kinetics of antibody-dependent cellular cytotoxicity (ADCC) of target cells treated with the same xenoantisera. Varying proportions of immune and nonimmune effector cells did not influence the amount of lysis of antibody-treated tumor cells. It would appear, therefore, that spleens from immunized animals contained cell populations that were capable of mediating both CMC and ADCC. Potentiation of CMC would appear to result from the preferential expression of ADCC effector cells; interaction of CMC effector cells was apparently hindered by the presence of antibody on the tumor cell surface. Immune complexes formed in antibody excess may also modify ADCC and the potentiation of CMC.     

Murine antibody-dependent cellular cytotoxicity to herpes simplex virus-infected target cells.

Freshly collected peritoneal cells (PC) and cultured spleen cells (SC) (but not fresh SC) from nonimmune mice could mediate antibody-dependent cellular cytotoxicity (ADCC) against herpes simplex virus (HSV)-infected cells in the presence of mouse or human sera containing antibody to HSV. PC also demonstrated variable natural killer cell cytotoxicity to infected cells. Both PC and cultured SC required high concentrations of antibody and high effector to target cell ratios for optimal ADCC. The time kinetics of the reaction appeared to depend on the state of activation of the effector cells. In both PC and SC populations, ADCC activity was limited to adherent cells, and was profoundly inhibited by particulate latex or silica. The murine effector cell found in PC and SC able to mediate ADCC to HSV-infected cells appears to be a macrophage.     

Cytotoxicity from cultured cells: analysis of precursors involved in generation of human cells mediating natural and antibody-dependent cell-mediated cytotoxicity.

Natural cell-mediated cytotoxicity of human peripheral blood lymphocytes natural killer (NK) against K-562 and antibody-dependent cellular cytotoxicity (ADCC) against Chang cells, as measured in a 4-hr ⁵¹Cr release assay, were both completely removed by depletion of Fc receptor-positive (FcR+) cells. After in vitro culture for 7 days, however, NK- and ADCC-like activities spontaneously regenerated. The nature of precursor cells was studied by examination of lymphocyte subpopulations required for generation of this cytotoxicity. After depletion of FcR+ cells from PBL, the following subpopulations were prepared: sheep erythrocyte rosette-forming cells (E+), surface membrane immunoglobulin-positive cells (SmIg+), and null cells (lacking E+, SmIg+, or FcR+ markers). Separate cell types or mixtures were cultured in vitro in medium containing 10% fetal calf serum for 7 days and then tested for NK and ADCC. Whereas unseparated FcR-depleted cells developed substantial cytotoxic activity, each of the subpopulations cultured alone was negative or had low activity. Addition of SmIg+ cells to other cell types had no effect; however, mixture of 80% E+ and 20% null cells resulted in optimal NK and ADCC. It is not presently clear which population the precursors were in. However, the requirement for proliferation by the null cell population but not by the E+ cells (as indicated by sensitivity to radiation and mitomycin C) suggested that the precursors for NK cells may be null cells.     

The effect of various cytokines on the in vitro induction of antibody-dependent cellular cytotoxicity in murine cells. Enhancement of IL-2-induced antibody-dependent cellular cytotoxicity activity by IL-1 and tumor necrosis factor-alpha

We have previously demonstrated that incubation with IL-2 can induce ADCC activity in murine cells and that this activity was mediated by asialo GM1+, FcR+ cells. In the present study we show that the cytokines IFN-alpha and IFN-gamma, TNF-alpha, and IL-1 alpha are unable to induce antibody-dependent cellular cytotoxicity (ADCC) in murine cells; however, TNF-alpha and IL-1 alpha could substantially augment the ADCC induced by IL-2. IL-1 increased the IL-2-induced ADCC activity in a dose-dependent fashion and in cells isolated from the thymus and spleen. The precursors of the ADCC induced by the combination of IL-1 and IL-2 were asialo GM1+ cells, similar to the precursor cells of IL-2-induced ADCC. The effect of IL-1 and TNF on ADCC was not the result of an increase in the FcR density on the cell surface or the result of an increase in the number of FcR+ cells although IL-1 increased the recovery of viable cells in culture. The main effect of IL-1 and TNF was the enhancement of the lytic ability of the IL-2 cultured cells as indicated by increased intra-cellular benzyloxycarbonyl L-lysine thiobenzylester-esterase activity. These results suggest that lymphokines such as IL-1 and TNF may synergize with IL-2 in the induction of ADCC and could thus potentially be useful for the immunotherapy of established tumors when combined with the administration of specific anti-tumor antibodies.     

Effects of inhibitors of C1q biosynthesis on macrophage Fc receptor subclass-mediated antibody-dependent cellular cytotoxicity and phagocytosis

We examined the effects of the inhibitors of C1q or collagen biosynthesis, 2,2'-dipyridyl (DP), and 3,4-dehydro-DL-proline (DHP) on murine macrophage (M phi) FcR subclass-mediated antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis of sheep erythrocyte targets. Oil-elicited peritoneal M phi from C3HeB/FeJ mice which were cultured for 24 hr with DP (0.08 or 0.10 mM) or DHP (0.8 or 1.0 mM) showed a significant decrease in FcR subclass-mediated ADCC for murine monoclonal IgG2a (FcRI) and IgG2b/IgG1 (FcRII) as well as for heterologous polyclonal IgG. These collagen inhibitors also blocked phagocytosis mediated by both IgG2a- and IgG2b-opsonized erythrocytes. DP was more potent than DHP in blocking FcR effector functions in a reversible fashion and neither inhibitor affected M phi C3b receptor function. Pretreatment of M phi with collagenase resulted in significant reduction in FcR-mediated ADCC and phagocytosis. The inhibition of M phi FcR subclass-mediated ADCC and phagocytosis by collagen C1q synthetic inhibitors or by collagenase treatment further confirms a functional relationship between cell-associated C1q and FcR-dependent functions.     

Enhanced modulation of antibodies coating guinea pig leukemic cells in vitro and in vivo. The role of Fc gamma R expressing cells.

We have investigated the antigenic modulation induced by a number of antibody fragments and derivatives directed against the idiotype of the surface Ig of the L2C guinea pig B lymphoblastic leukemia, and studied the effects upon such modulation of the simultaneous presence of cells expressing Fc gamma receptors (FcR). In vitro studies confirmed previous work showing that antibody bivalency is required to induce modulation in vitro in simple systems. However, in the presence of isolated Kupffer cells, Fc-containing univalent antibodies were found to induce significant antigenic modulation, and the modulation induced by intact IgG was also found to be more rapid and extensive. Fragments that did not contain Fc regions behaved similarly in the presence or absence of Kupffer cells. Further investigations demonstrated that all three classes of human FcR can mediate modulation enhancement, and suggest that the mechanism involves indirect cross-linking of cell surface Ag via the antibody and effector cell FcR. In vivo studies showed that univalent antibody derivatives containing Fc regions did induce antigenic modulation, but that this was significantly reduced in comparison with bivalent antibodies, confirming their potential advantage for immunotherapy.     

Chaperone activity of recombinant maize chloroplast protein synthesis elongation factor, EF-Tu.

The protein synthesis elongation factor, EF-Tu, is a protein that carries aminoacyl-tRNA to the A-site of the ribosome during the elongation phase of protein synthesis. In maize (Zea mays L) this protein has been implicated in heat tolerance, and it has been hypothesized that EF-Tu confers heat tolerance by acting as a molecular chaperone and protecting heat-labile proteins from thermal aggregation and inactivation. In this study we investigated the effect of the recombinant precursor of maize EF-Tu (pre-EF-Tu) on thermal aggregation and inactivation of the heat-labile proteins, citrate synthase and malate dehydrogenase. The recombinant pre-EF-Tu was purified from Escherichia coli expressing this protein, and mass spectrometry confirmed that the isolated protein was indeed maize EF-Tu. The purified protein was capable of binding GDP (indicative of protein activity) and was stable at 45 degrees C, the highest temperature used in this study to test this protein for possible chaperone activity. Importantly, the recombinant maize pre-EF-Tu displayed chaperone activity. It protected citrate synthase and malate dehydrogenase from thermal aggregation and inactivation. To our knowledge, this is the first observation of chaperone activity by a plant/eukaryotic pre-EF-Tu protein. The results of this study support the hypothesis that maize EF-Tu plays a role in heat tolerance by acting as a molecular chaperone and protecting chloroplast proteins from thermal aggregation and inactivation.     

Mobility and density of AgB, "Ia", and Fc receptors on the surface of lymphocytes from young and old rats.

Analysis of spleen cell populations from old Lewis rats (greater than 24 months) and from young Lewis rats (3 to 4 months) in a fluorescence-activated cell sorter indicated that with aging there is a loss of brightly stained Ia and Fc receptor- (FcR) positive cells. The density of AgB, Ia, and FcR was diminished on the surface of cells from old rats. The rate of capping of all three membrane proteins was slower on cells from old rats. Colchicine treatment allows capping of AgB with a single ligand only in young rats. Fluorescence photobleach recovery experiments (FPR) show that the fluidity of the lymphocyte membrane from old rats is diminished and the lateral diffusion of AgB is decreased. The colchicine and FPR experiments suggest that the changes in capping in old rats are due to, in part, alterations in membrane fluidity and cytoskeletal function.     

Polyadnylic acid sequences in RNA able to transfer specific delayed type hypersensitivity in vitro.

Antibody-depedent cell-mediated cytotoxicity (ADCC) could be initiated without protein synthesis [human peripheral blood lymphocytes as effector cells incubated with 10^?3M cycloheximide, (Cy)], although the reaction did not achieve its full lytic ability. This partial inhibition of ADCC was dependent on the dose of Cy. Both ADCC and protein synthesis returned to normal values after removal of the inhibitor. The kinetics of the reaction carried out by Cy-treated effector cells for short periods was similar to that of controls. After this time, the percentage of lysed target cells increased continuously in controls, while the cytotoxiciy of Cy-treated effector cells reached a plateau. When effector cells carried out ADCC in the presence of Cy, their lytic mechanism was “wasted,” and it could be recovered only by removal of the inhibitor. Our results indicate that effector cells have a preformed lytic mechanism operative in ADCC. This lytic mechanism is consumed during the reaction and its recovery requires protein synthesis.     

Two distinct mechanisms of cytotoxicity by porcine alveolar macrophages in antibody-dependent and immobilized immune complex-dependent cellular cytotoxicity

The mechanisms of cytotoxicity by porcine pulmonary alveolar macrophages (PAM) involved in antibody-dependent cellular cytotoxicity (ADCC) and immobilized immune complex-dependent cellular cytotoxicity (IIC-DCC) were investigated. The results indicate that IIC-DCC was inhibited by both catalase and thioglycollate broth whereas these peroxide scavengers had no effect on ADCC in an 18-hr chromium-release assay. Furthermore, it was found that when the PAM and red blood cell targets were cross-linked with PHA, catalase still completely eliminated IIC-DCC and had no effect on ADCC, which suggests that catalase is able to penetrate the lytic site when the effector and targets are cross-linked as in ADCC. The presence of cytochalasin B, which inhibits internalization of immune complexes by PAM and presumably prevents intracellular killing, also had no effect on the differential susceptibility of IIC-DCC and ADCC to catalase. Finally, it is shown that the nonspecific cytotoxicity generated by exposing PAM to immune complexes in suspension in conjunction with cytochalasin B, so that the immune complex-bound Fc receptor (FcR) cannot be internalized, also was susceptible to catalase. These data show that the lytic mechanism involved in the nonspecific cytotoxicity generated by exposing PAM to immobilized immune complexes or immune complexes in suspension in conjunction with cytochalasin B, both of which prevent the internalization of immune complex-bound FcR, is mediated solely by peroxide whereas the lytic mechanism involved in ADCC operates, at least partially, through a peroxide-independent mechanism.     

Apparent sensitivity of human K lymphocytes to the spatial orientation and organization of target cell-bound antibodies as measured by the efficiency of antibody-dependent cellular cytotoxicity (ADCC)

Although monoclonal antibodies (mAb) can elicit potent ADCC by human K lymphocytes, different mAb, even of the same antibody subclass or even of the same target antigen specificity, vary considerably as to their efficiency in eliciting ADCC. The extensive variability in ADCC efficiencies of murine IgG2a mAb is analyzed here. In cold-target inhibition experiments it was found that only cells coated with "ADCC-efficient" IgG2a mAb, and not "ADCC-inefficient" IgG2a mAb, inhibit K effector cell lysis of radiolabeled target cells by ADCC. This result indicates that the spatial orientation of the antibodies on the target cell membrane influences the net efficiency of ADCC reactions by affecting the efficiency of interaction between antibody and the Fc receptors (FcR) of K cells. It is proposed that a "favorable" orientation of antibodies on the target cell membrane is required for efficient ADCC reactions. This proposal is directly supported by the observation that one IgG2a mAb (20.8.4), which cross-reacts with several different H-2 alloantigens, was found to elicit efficient ADCC only when bound to certain of its possible target cell antigens. It was also observed in these studies that the organization of antibodies on a target cell membrane influences the net efficiency of ADCC reactions. It is proposed that a "favorable" antibody organization on the target cell membrane is also required for efficient ADCC reactions. This proposal is supported by the observation that certain antihuman beta 2m (anti-Hu beta 2m) IgG2a mAb, which elicit efficient ADCC lysis of human target cells, fail to elicit the lysis of murine cells having Hu beta 2m molecules coupled randomly to their external membrane surfaces. The differences in the way the Hu beta 2m was organized on the surfaces of the human cells and the murine-Hu beta 2m cell conjugates presumably caused differences in the way the bound antibodies were organized on the cell surfaces, which in turn resulted in the ADCC efficiency differences observed for the same mAb with the different target cell types. Because ADCC reactions appear to be sensitive to both the orientation and the organization of cell surface-bound antibodies, certain types of structural alterations or variations in the membrane molecules (relative to other neighboring structures on the target cell membrane) are potentially detectable by quantitative differences or variations in ADCC reactions.     

Ultrastructure of antibody dependent cellular cytotoxicity in HSV 1 infected and uninfected Chang liver cells

The binding and ultrastructural features of antibody dependent cellular cytotoxicity (ADCC) mediated by human peripheral blood lymphocytes were studied in herpes simplex virus type I (HSV-1) infected Chang liver (CL) cells plus human anti-HSV-1 serum, and in uninfected CL cells plus guinea pig anti-CL antiserum. Non-cytolytic controls included target cells treated with normal serum in place of sensitized targets and heat shocked lymphocytes instead of normal lymphocytes. By transmission electron microscopy, target cell membranes were either broadly indented by effector cells or locally invaginated by means of effector cell filopodia. In neither case did the indentation appear to break the plasma membrane of the target. Control preparations showed only non-indented areas of simple membrane contact. By scanning electron microscopy, the effector lymphocytes in both the active ADCC and normal serum control preparations had a sparse distribution of short microvilli over their surfaces. The majority of heat shock control lymphocytes appeared normal, but 12-20% demonstrated surface patches devoid of microvilli. The hypothesis that ADCC may involve a three-step process is discussed.     

Evidence that natural cytotoxicity and antibody-dependent cellular cytotoxicity are mediated in humans by the same effector cell populations.

The present study strongly suggests that, in humans, natural killer (NK) activity and antibody-dependent cell-mediated cytotoxicity (ADCC) are mediated by the same effector cell population. This is supported by two different experimental approaches. First, competition for NK effector cells was accompanied by simultaneous inhibition of ADCC activity. Target cells sensitive to NK activity were capable of inhibiting specifically an ADCC assay in cold target competition experiments. Second, specific removal of NK cells on monolayers formed by target cells sensitive to NK activity caused simultaneous depletion of ADCC effector cells. In association with the removal on the monolayers of effector cells for ADCC as well as NK activity, we also found a significant depletion of cells bearing Fc gamma receptors.