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)beta(2 ) integrin. It activates T cells through outside-in signaling, but pol ymorphonuclear leukocytes (PMN) are reported to be refractory to ICAM- 3 stimulation, We found that engagement of ICAM3 by a mAb (CAL3.10), w hich binds in the region where alpha(L)beta(2) integrin binds, activat es PMN homotypic aggregation and adhesion to surfaces. These functiona l changes were due to ICAM-3 outside-in signaling because aggregation and adhesion were beta(2) integrin-dependent, tyrosine kinase and prot ein kinase C activities were activated, and there was a reorganization of the cytoskeleton. This reorganization and kinase activity was requ ired for ICAM-3-, but not FMLP-, induced aggregation. This is not an F c-mediated event as an appropriate anti-ICAM-3 F(ab')(2) fragment stil l induced aggregation, Another anti-ICAM-3 Ab (HP2/19), which activate s T cells, did not activate PMN. Strikingly, anti-ICAM-3 did not induc e degranulation or cause an increase in surface beta(2) integrin expre ssion, so adhesion and aggregation were due solely to the activation o f the constitutively expressed beta(2) integrins. Aggregation in respo nse to ICAM-3, but not FMLP, was compromised at lower cell densities, showing that beta(2) integrin recruitment enhances aggregation under s uboptimal conditions. We conclude that engagement of ICAM-3 stimulates PMN as well as T cells, but that the appropriate epitope varies betwe en these two cells, ICAM-3 outside-in signaling reorganizes the cytosk eleton without causing degranulation, induces serine and tyrosine kina se activation, and activates existing surface beta(2) integrins to a p roadhesive state.