Journal
JOURNAL OF IMMUNOLOGY
Volume 182, Issue 9, Pages 5654-5662Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.0803942
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Funding
- National Institutes of Health [HL054164, AI067502]
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Fc gamma receptor (Fc gamma R)-mediated phagocytosis is known to require tyrosine kinases (TKs). We identified c-Cbl and Cbl-b as proteins that undergo tyrosine phosphorylation during phagocytosis. Cbl-deficient macrophages displayed enhanced Fc gamma R-mediated signaling and phagocytosis. Surprisingly, binding of IgG-coated targets (EIgG) was also enhanced. c-Cbl-deficient macrophages expressed less Fc gamma RIIb, the inhibitory Fc gamma receptor; however, this did not account for enhanced target binding. We isolated the function of one Fe receptor isoform, Fc gamma RI, using IgG2a-coated targets (EIgG2a). Cbl-deficient macrophages demonstrated a disproportionate increase in binding EIgG2a, suggesting that signal strength regulates binding efficiency toward opsonized targets. In resting cells, Fc gamma RI colocalized with the Src family TK Hck in F-actin-rich structures, which was enhanced in Cbl-deficient macrophages. Target binding was sensitive to TK inhibitors, profoundly inhibited following depletion of cholesterol, and ablated at 4 degrees C or in the presence of inhibitors of actin polymerization. Sensitivity of EIgG binding to cytoskeletal disruption was inversely proportional to opsonin density. These findings challenge the view that Fc gamma R-mediated binding is a passive event. They suggest that dynamic engagement of TKs and the cytoskeleton enables macrophages to serve as cellular Venus fly traps, with the capacity to capture phagocytic targets under conditions of limiting opsonin density. The Journal of Immunology, 2009, 182: 5654-5662.
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