Mapping and comparison of the interaction sites on the Fc region of IgG responsible for triggering antibody dependent cellular cytotoxicity (ADCC) through different types of human Fcγ receptor (original) (raw)
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Cytotoxicity mediated by human Fc receptors for IgG
Immunology Today, 1989
Cylotoxidty mediated by human Fc m The, c receptors for IgG(Fc,IR) play a major role in the removal of antibody-coated infectious agents and may be important molecules for triggering cytotoxidty of tumor cells; they may also serve as an en~ for infect'on of Fc~R-bearing cells by viral ~nduding HIV and Dengue), and perhaps other infectious agents. Although cen~l to immune defense, an understanding of the role of these Fc~iR in cytotoxicity has been complicated in part by the presence of several biochemical~ distinct types of receptor that have different distn'butions, specificities, affini~es and modes of activation for killing. The development of monodonal antibodies specific for F~R on human !eukocites has established the existence of three distinct Fc~IR and furthermore has helped clarify the function of each of these receptors. In this review, Michael Fanger and colleagues discuss the use of Fc,tR-specific mAb and the hybridoma cell lines that produce them in examining the ability of each of these unique receptors to mediate killing of tumor and red cell targets. In pa~'cular, the use of serf-directed hybridoma cells as a model of tumor-cell killing and of bi-specific antibodies to link target cells to effector cells through the different Fc~IR is discussed. The results of these studies suggest that the ability of a given Fc~IR to ~igger killing is sometimes dependent on the type of Fc~IR, but is also rnarked~/ influenced by the type of target cell and by the nature and state of activation of the effector cell. Antibody-dependent cell-mediated cytotoxicity (ADCC) is performed by a variety of cell populations and requires the recognition of an antibody-coated target by Fc receptors on the effector ceii. Aithough ADCC is primarily dependent on IgG antibodies, its efficiency and relevance has been shown to vary with the effector cell population, the state of activation of this population, the species and isotype of the antibody, the nature of the target cell and the specificity or density of coating of the anti-target-cell antibody. Many of the variables result from the presence of different types of Fc receptors for IgG (Fc~/R) that are differentially expressed and modulated on different effector cell populations. Moreover, when presented as a multivalent array on a target cell, antibodies of different isotypes may bind more or less efficiently to more than one type of Fc~R and have variable ability to trigger function. Three distinct classes of Fc-yR (Table 1) have been recognized on human leukocytes TM. The production of monoclonal antibodies (rnAb) and cDNA probes to all three human Fc~/R has confirmed this receptor heterogeneity, and now permits independent analysis of each class of Fc~R. ::)istribuUon and properties of Fc~R There are three classes of human Fc~/R. Fc~/RI is a 70 kDa glycopro~.ein (recognized by mAb 32 (Ref. 5), mAbs 22, 44, 62 and 197 (Guyre, P.
Scandinavian Journal of Immunology, 1989
We investigated the cytotoxieity of human monocytes mediated by two types of receptors for the Fe portion of IgG. FcyRI and FcyRII. Erythrocylessensitized with human IgG {EA-human IgG) were used lo assay FcyRI function, and erythrocytes sensitized wiih mouse IgGl (EAmouse IgGl) were used to assay FcyRII. Both types of FeyR were observed lo mediate antibody-dependent cell-mediated cytatoxiciiy (ADCC). which was further eharaeterized by using different monoclonal anti-FcyR antibodies (MoAb) and monomerie IgG. Lysis of EA-human IgG was inhibited by both monomcric human IgG and mouse lgG2a in a dosedependenl way. and also hyanti-FcyRI MoAb 10.1. Cytolysisof EA-mouse IgGl was inhibited by monomerie mouse IgGl andby twoanti-FcyRII MoAb. IV.3andCIKM5. Antibodies of the mouse IgG2b isotype affected neither type of ADCC. The effectiveness of eytotoxicity mediated by either of the FcyR was studied by means of targets sensitized with a calibrated number of IgG molecules. At least 20 times more IgG molecules per target cell were necessary to obtain half-maximal cytotoxicity mediated by FcyRII than for FeyRI-medialed eytolysis. Furthermore, the previously described polymorphism of FcyRII was also reflected in FcyRII-dependent cytotoxicity. These studies demonstrate that FcyRI! can mediate ADCC, although a higher degree of target cell sensitization h required than for FcyRI-mediated ADCC.
Subclass specificity of the Fc receptor for human IgG on K562*1
Cellular Immunology, 1988
The erythroleukemic cell line K562 bears a 40-kDa Fc receptor (FcyRII) serologically related to and with a similar molecular weight as the FcyR present on a broad range of leukocytes. The human IgG subclass specificity of the FcyR on KS62 was investigated using IgG aggregates of defined size, obtained from purified human myeloma proteins. The monoclonal antibody IV.3, which reacts with the FcyRII present on various cell types, totally prevented binding of '251-IgG2 trimers to K562. Experiments with radiolabeled IgG2 trimers showed that K562 cells bound a mean of 156,764 + 9895 molecules per cell with an association constant (k) of 1.8 + 0.7 X 10' M-'. Similar results were obtained with IgG3 oligomers. IgGs and IgG2 trimers were about twoto threefold more effective in inhibiting binding of '*'I-IgG2 trimers to K562 than IgG, and IgG., trimers. These results were confirmed by inhibition experiments using IgG monomers. The subclass specificity of the FcyRII on K562 (i.e., IgG2 = IgG, > IgG, = IgG4) is quite distinct from the one reported for the FcrRI and III of human cells (i.e., IgG, = IgG, > IgG, and I@&).
Immunology
It is shown that the Fc receptor for IgG on lymph node cells recognizes IgG molecules of mouse IgG1, IgG2a and IgG2b subclasses. The presence of an intact CH3 domain is required to bind IgG to the Fc receptors. While monomeric IgG molecules are shown to bind to Fc receptors, heat aggregated IgG was found to bind more efficiently. The various forms of IgM molecules investigated show only weak or no binding in comparison. The significance of these results is discussed with relevance to the possible biological function of the Fc receptors on lymphocytes.
Subclass specificity of the Fc receptor for human IgG on K562
Cellular Immunology, 1988
The erythroleukemic cell line K562 bears a 40-kDa Fc receptor (FcyRII) serologically related to and with a similar molecular weight as the FcyR present on a broad range of leukocytes. The human IgG subclass specificity of the FcyR on KS62 was investigated using IgG aggregates of defined size, obtained from purified human myeloma proteins. The monoclonal antibody IV.3, which reacts with the FcyRII present on various cell types, totally prevented binding of '251-IgG2 trimers to K562. Experiments with radiolabeled IgG2 trimers showed that K562 cells bound a mean of 156,764 + 9895 molecules per cell with an association constant (k) of 1.8 + 0.7 X 10' M-'. Similar results were obtained with IgG3 oligomers. IgGs and IgG2 trimers were about twoto threefold more effective in inhibiting binding of '*'I-IgG2 trimers to K562 than IgG, and IgG., trimers. These results were confirmed by inhibition experiments using IgG monomers. The subclass specificity of the FcyRII on K562 (i.e., IgG2 = IgG, > IgG, = IgG4) is quite distinct from the one reported for the FcrRI and III of human cells (i.e., IgG, = IgG, > IgG, and I@&).
Cellular Immunology, 1980
The mechanisms of Fc receptor blocking by anti-Ig, anti-Ia, and anti-B2 microglobulin (anti-B2Mi) antibodies were compared on human peripheral blood mononuclear cells. The results suggest that Fc receptors were "co-endocytosed" with sIg/anti-Ig and Is/anti-Ia complexes, while they were "co-shed" with BZMi/anti-B2Mi complexes during the incubation with the antibodies at 37'C. Fc receptors recovered after the blocking by anti-B2Mi or anti-Ig, but not after anti-Ia or heat-aggregated human IgG(Agg Hg) treatment. Lymphocytes were able to replace their endocytosed or shed Fc receptors presumably from a preformed cytoplasmic receptor pool. Anti-Ia antibodies and AggHg probably exhausted this Fc receptor pool or inhibited its transport to the membrane causing an irreversible inhibition of Fc receptor expression on the appropriate cells. ' Abbreviations used: PBMC, peripheral blood mononuclear cells; PBS, phosphate-buffered saline; FCS, fetal calf serum; EA, erythrocytes coated with antibody; E, sheep erythrocytes; cEA, chicken erythrocytes coated with antibody; oEA, bovine erythrocytes coated with antibody; E-cEAR, double rosettes binding E and cEA; RFC, rosette-forming cells; EAR, rosette formed by antibody-coated erythrocytes; sIg, surface immunoglobulins; Ia, I region-associated antigens; FcR, Fc receptors; BZMi, B2 microglobulins; NS, normal sera; FITC, fluorescein isothiocyanate; CH, cycloheximide; AggHG, heat-aggregated human IgG; C3R, receptors binding the third complement factor; ADCC, antibodymediated cellular cytotoxicity; oEAR, rosettes with antibody-coated bovine erythrocytes; cEAR, rosettes with antibody-coated chicken erythrocytes.
Immunology Letters, 1986
Domain deleted paraproteins are suitable tools to study the interaction between IgG domains and Fc receptor (FcR) binding sites. The effect of the C gamma 2 or C gamma 3 domain deleted paraproteins was compared on antibody dependent cellular cytotoxicity (ADCC) and on FcR mediated rosette formation. The C gamma 2 domain deleted paraprotein (TIM) had no significant effect on lymphocyte or monocyte mediated ADCC, while the C gamma 3 domain deleted paraprotein (SIZ) inhibited both types of cytotoxicity. FcR dependent rosette formation was also inhibited by SIZ but TIM was ineffective. The data further confirm our previous results suggesting a significant role of C gamma 2 domain in the transfer of killing signal in ADCC and that of C gamma 3 domain in the high affinity binding to lymphocyte FcR.