Ligand inhibition studies on the role of Fc receptors in antibody-dependent cell-mediated cytotoxicity.
Subjection of human peripheral blood lymphocytes to a temp shift from 4 to 37 degrees C resulted in a shedding of Fc receptors (termed FcRI) from 40-50% of FcR-positive cells followed by their re-expression within 4 hr; a phenomenon which had no effect on the cells' antibody-dependent killing capacity. Removal of lymphocytes having an immobile form of the Fc receptor resistant to the effects of the temp shift (termed FcRII), or removal of lymphocytes bearing both FcRI and FcRII, resulted in a similar amount of reduction in ADCC activity. This was attributed, therefore, to the loss of FcRII-positive cells. The influence of isolated (shedded) FcRI and Clq on ADCC activity was investigated. Soluble FcRI was shown to inhibit ADCC mediated through the immobile Fc receptors (FcRII), despite its lack of an ability to block EA rosette formation through these receptors. Clq also had a dose-dependent inhibitory effect on ADCC. These observations are consistent with earlier findings that FcRII possesses two active binding sites; and suggest that a prerequisite for killing in ADCC is the interaction of these with the C gamma 2 and C gamma 3 domains. The ability of synthetic peptides representative of human gamma 1-chain sequences to inhibit ADCC was determined, in an attempt to locate those sites within the IgG antibody Fc region involved in interaction with two FcR binding sites. Preliminary evidence was obtained to suggest that one of these is situated within the C gamma 2 domain, in the region of residues 274 (Lys)-294 (Glu).
D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D001665:Binding Sites; D003166:Complement Activating Enzymes / Q000276:immunology; D015922:Complement C1q; D006801:Humans; D008214:Lymphocytes / Q000276:immunology; D010455:Peptides / Q000494:pharmacology; D011961:Receptors, Fc / Q000276:immunology*; D012397:Rosette Formation
D010455:Peptides; D011961:Receptors, Fc; D015922:Complement C1q; D003166:Complement Activating Enzymes