Journal
JOURNAL OF IMMUNOLOGY
Volume 164, Issue 1, Pages 350-360Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.164.1.350
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Funding
- NATIONAL CENTER FOR RESEARCH RESOURCES [S10RR009145] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI024322, R37AI024322] Funding Source: NIH RePORTER
- NCRR NIH HHS [1S10RR09145-01] Funding Source: Medline
- NIAID NIH HHS [AI24322] Funding Source: Medline
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Human neutrophils (PMNs) express two receptors for the Fc domain of IgG: the transmembrane Fc gamma RIIA, whose cytosolic sequence contains an immunoreceptor tyrosine-based activation motif, and the GPI-anchored Fc gamma RIIIB. Cross-Linking of Fc gamma RIIIB induces cell activation, but the mechanism is still uncertain. We have used mAbs to cross-link selectively each of the two receptors and to assess their signaling phenotypes and functional relation. Cross-linking of Fc gamma RIIIB induces intracellular Ca2+ release and receptor capping. The Ca2+ response is blocked by wortmannin and by N,N-dimethylsphingosine, inhibitors of phosphatidylinositol 3-kinase and sphingosine kinase, respectively. Identical dose-response curves are obtained for the Ca2+ release stimulated by cross-linking Fc gamma RIIA, implicating these two enzymes in a common signaling pathway. Wortmannin also inhibits capping of both receptors, but not receptor endocytosis. Fluorescence microscopy in double-labeled PMNs demonstrates that Fc gamma RIIA colocalizes with cross-linked Fc gamma RIIIB. The signaling phenotypes of the two receptors diverge only under frustrated phagocytosis conditions, where Fc gamma RIIIB bound to substrate-immobilized Ab does not elicit cell spreading. We propose that Fc gamma RIIIB signaling is conducted by molecules of Fc gamma RIIA that are recruited to protein/lipid domains induced by clustered Fc gamma RIIIB and, thus, are brought into juxtaposition for immunoreceptor tyrosine-based activation moth phosphorylation and activation of PMNs.
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