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Engagement of ICAM-3 Activates Polymorphonuclear Leukocytes: Aggregation Without Degranulation or ß₂ Integrin Recruitment¹

Michael J. Feldhaus^2,*, Julie M. Kessel, Guy A. Zimmerman and Thomas M. McIntyre^3,*,

Departments of ^* Pathology, Medicine, and Pediatrics, University of Utah, Salt Lake City, UT 84112

ICAM-3 is a preferred counterreceptor for the leukocyte _Lß₂ 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 _Lß₂ 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 ß₂ 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 ß₂ integrin expression, so adhesion and aggregation were due solely to the activation of the constitutively expressed ß₂ integrins. Aggregation in response to ICAM-3, but not FMLP, was compromised at lower cell densities, showing that ß₂ 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 ß₂ integrins to a proadhesive state.

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