A novel role for IgG-Fc. Transductional potentiation for human high affinity Fc gamma receptor (Fc gamma RI) signaling.
Human type 1 Fc gamma receptors (Fc gamma RI) bind with high affinity (Kd = approximately 10(-9) M) Fc regions of monomeric IgG1 and IgG3. As demonstrated in this report, interaction of IgG-Fc with the ligand binding site on Fc gamma RI alters its capacity for aggregation-dependent signaling. This Fc-dependence was demonstrated in normal monocytes and U937-10.6 cells exposed to monomeric IgG and then to anti-Fc gamma RI F(ab')2 that cross-link the receptor. Using O2- production to measure cell signaling, we found that binding by high affinity IgGs of various species, as well as by murine hybrid IgGs containing only one high affinity heavy chain, resulted in a marked increase in Fc gamma RI-mediated signaling. Preaggregated Fc gamma RI/IgG had a ratio of one. IgG binding after aggregation of unligated Fc gamma RI did not restore signaling. Dose responses indicated that concentrations of IgG that saturated Fc gamma RI optimized transductional activity. The inclusion of unligated with ligated Fc gamma RI in aggregates depressed activity, indicating a lack of trans-activation of unligated Fc gamma RI. Significantly, IgG-binding markedly increased aggregation-dependent tyrosine phosphorylation of Fc gamma RI gamma-chains and the association of tyrosine phosphorylated Syk. Thus, the consequences of IgG-Fc binding were increases in aggregation-dependent phosphorylation of Fc gamma RI gamma-chains, recruitment of pp72Syk to Fc gamma RI, and signaling of the NADPH oxidase pathway.
Pfefferkorn
L C
LC
Department of Microbiology, Dartmouth Medical School, Lebanon, New Hampshire 03756, USA.
van de Winkel
J G
JG
Swink
S L
SL
D000911:Antibodies, Monoclonal / Q000276:immunology; D002460:Cell Line; D004792:Enzyme Precursors / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D010766:Phosphorylation; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D017452:Receptors, IgG / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D000072377:Syk Kinase
D000911:Antibodies, Monoclonal; D004792:Enzyme Precursors; D007074:Immunoglobulin G; D047908:Intracellular Signaling Peptides and Proteins; D017452:Receptors, IgG; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase