Calicum microdomains form within neutrophils at the neutrophil-tumor cell synapse: role in antibody-dependent target cell apoptosis.
Ca(2+) messages are broadly important in cellular signal transduction. In immune cells, Ca(2+) signaling is an essential step in many forms of activation. Neutrophil-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) is one form of leukocyte activation that plays an important role in tumor cell killing in vitro and in patient care. Using fluorescence methodologies, we found that neutrophils exhibit Ca(2+) signals during ADCC directed against breast fibrosarcoma cells. Importantly, these signals were localized to Ca(2+) microdomains at the neutrophil-to-tumor cell interface where they display dynamic features such as movement, fusion, and fission. These signals were blocked by the intracellular Ca(2+) buffer BAPTA. At the neutrophil-tumor cell synapse, the neutrophil's cytoplasm was enriched in STIM1, a crucial mediator of Ca(2+) signaling, whereas the Ca(2+)-binding proteins calbindin and parvalbumin were not affected. Our findings suggest that Ca(2+) microdomains are due to an active signaling process. As Ca(2+) signals within neutrophils were necessary for specific tumor cell apoptosis, a central role of microdomains in leukocyte-mediated tumor cell destruction is indicated.
Clark
Andrea J
AJ
Department of Ophthalmology and Visual Sciences, The University of Michigan Medical School, 1000 Wall Street, Ann Arbor, MI 48105, USA.
Diamond
Michelle
M
Elfline
Megan
M
Petty
Howard R
HR
D000920:Antibody-Dependent Cell Cytotoxicity; D017209:Apoptosis / Q000276:immunology*; D001943:Breast Neoplasms; D002118:Calcium / Q000502:physiology*; D015220:Calcium Channels; D002448:Cell Adhesion; D002459:Cell Fusion; D045744:Cell Line, Tumor; D005260:Female; D005354:Fibrosarcoma; D006801:Humans; D007365:Intercellular Junctions / Q000502:physiology*; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000276:immunology; D021962:Membrane Microdomains / Q000502:physiology*; D009504:Neutrophils / Q000276:immunology* / Q000502:physiology; D000071737:Stromal Interaction Molecule 1
D015220:Calcium Channels; D008562:Membrane Glycoproteins; C100757:Stim1 protein, mouse; D000071737:Stromal Interaction Molecule 1; D002118:Calcium