Engagement of ICAM-3 activates polymorphonuclear leukocytes: aggregation without degranulation or beta 2 integrin recruitment.
ICAM-3 is a preferred counterreceptor for the leukocyte alpha(L)beta2 integrin. It activates T cells through outside-in signaling, but polymorphonuclear leukocytes (PMN) are reported to be refractory to ICAM-3 stimulation. We found that engagement of ICAM-3 by a mAb (CAL3.10), which binds in the region where alpha(L)beta2 integrin binds, activates PMN homotypic aggregation and adhesion to surfaces. These functional changes were due to ICAM-3 outside-in signaling because aggregation and adhesion were beta2 integrin-dependent, tyrosine kinase and protein kinase C activities were activated, and there was a reorganization of the cytoskeleton. This reorganization and kinase activity was required for ICAM-3-, but not FMLP-, induced aggregation. This is not an Fc-mediated event as an appropriate anti-ICAM-3 F(ab')2 fragment still induced aggregation. Another anti-ICAM-3 Ab (HP2/19), which activates T cells, did not activate PMN. Strikingly, anti-ICAM-3 did not induce degranulation or cause an increase in surface beta2 integrin expression, so adhesion and aggregation were due solely to the activation of the constitutively expressed beta2 integrins. Aggregation in response to ICAM-3, but not FMLP, was compromised at lower cell densities, showing that beta2 integrin recruitment enhances aggregation under suboptimal conditions. We conclude that engagement of ICAM-3 stimulates PMN as well as T cells, but that the appropriate epitope varies between these two cells. ICAM-3 outside-in signaling reorganizes the cytoskeleton without causing degranulation, induces serine and tyrosine kinase activation, and activates existing surface beta2 integrins to a proadhesive state.
Feldhaus
M J
MJ
Department of Pathology, University of Utah, Salt Lake City 84112, USA.
Kessel
J M
JM
Zimmerman
G A
GA
McIntyre
T M
TM
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD; D000943:Antigens, Differentiation; D002118:Calcium / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000276:immunology / Q000378:metabolism*; D002449:Cell Aggregation / Q000276:immunology; D015550:Cell Degranulation / Q000276:immunology*; D003594:Cytoplasmic Granules / Q000276:immunology / Q000378:metabolism; D003599:Cytoskeleton / Q000276:immunology / Q000378:metabolism; D000939:Epitopes / Q000276:immunology; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism* / Q000502:physiology; D018375:Neutrophil Activation / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation; D011940:Receptor Aggregation / Q000276:immunology*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D014443:Tyrosine / Q000378:metabolism
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D015815:Cell Adhesion Molecules; D000939:Epitopes; C483616:ICAM3 protein, human; D016169:Lymphocyte Function-Associated Antigen-1; D014443:Tyrosine; D012694:Serine; D002118:Calcium