Mac-1 (CD11b/CD18) is essential for Fc receptor-mediated neutrophil cytotoxicity and immunologic synapse formation.
Receptors for human immunoglobulin (Ig)G and IgA initiate potent cytolysis of antibody (Ab)-coated targets by polymorphonuclear leukocytes (PMNs). Mac-1 (complement receptor type 3, CD11b/CD18) has previously been implicated in receptor cooperation with Fc receptors (FcRs). The role of Mac-1 in FcR-mediated lysis of tumor cells was characterized by studying normal human PMNs, Mac-1-deficient mouse PMNs, and mouse PMNs transgenic for human FcR. All PMNs efficiently phagocytosed Ab-coated particles. However, antibody-dependent cellular cytotoxicity (ADCC) was abrogated in Mac-1(-/-) PMNs and in human PMNs blocked with anti-Mac-1 monoclonal Ab (mAb). Mac-1(-/-) PMNs were unable to spread on Ab-opsonized target cells and other Ab-coated surfaces. Confocal laser scanning and electron microscopy revealed a striking difference in immunologic synapse formation between Mac-1(-/-) and wild-type PMNs. Also, respiratory burst activity could be measured outside membrane-enclosed compartments by using Mac-1(-/-) PMNs bound to Ab-coated tumor cells, in contrast to wild-type PMNs. In summary, these data document an absolute requirement of Mac-1 for FcR-mediated PMN cytotoxicity toward tumor targets. Mac-1(-/-) PMNs exhibit defective spreading on Ab-coated targets, impaired formation of immunologic synapses, and absent tumor cytolysis.
van Spriel
A B
AB
Immunotherapy Laboratory and Medarex Europe, University Medical Center Utrecht, The Netherlands.
Leusen
J H
JH
van Egmond
M
M
Dijkman
H B
HB
Assmann
K J
KJ
Mayadas
T N
TN
van de Winkel
J G
JG
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000920:Antibody-Dependent Cell Cytotoxicity; D001943:Breast Neoplasms / Q000473:pathology; D018821:CD18 Antigens / Q000502:physiology*; D002176:Candida albicans; D002277:Carcinoma / Q000473:pathology; D002448:Cell Adhesion; D003433:Crosses, Genetic; D003602:Cytotoxicity, Immunologic; D005089:Exocytosis; D005260:Female; D005966:Glucuronidase / Q000378:metabolism; D006801:Humans; D007070:Immunoglobulin A / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D007781:Lactoferrin / Q000378:metabolism; D016177:Macrophage-1 Antigen / Q000502:physiology*; D008561:Membrane Fusion; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009252:NADPH Dehydrogenase / Q000378:metabolism; D019255:NADPH Oxidases; D009504:Neutrophils / Q000276:immunology / Q000502:physiology* / Q000648:ultrastructure; D009895:Opsonin Proteins / Q000276:immunology; D010587:Phagocytosis; D010750:Phosphoproteins / Q000378:metabolism; D021381:Protein Transport; D011961:Receptors, Fc / Q000502:physiology*; D016897:Respiratory Burst; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D018821:CD18 Antigens; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D016177:Macrophage-1 Antigen; D026901:Membrane Transport Proteins; D009895:Opsonin Proteins; D010750:Phosphoproteins; D011961:Receptors, Fc; D019255:NADPH Oxidases; C086986:CYBA protein, human; D009252:NADPH Dehydrogenase; D005966:Glucuronidase; D007781:Lactoferrin