Yvette van Kooyk

On the mode of action of LFA-1

Abstract The leukocyte function-associated molecule 1 (LFA-1) plays a key role in cell adhesion among leukocytes and between leukocytes and other cell types. Although two ligands of LFA-1 have been identified, namely the intercellular adhesion molecules 1 (ICAM-1) and 2 (ICAM-2), the exact mechanism by which LFA-1 binds to and detaches from its ligand(s) has remained obscure. Based on novel findings Carl Figdor, Yvette van Kooyk and Gerrit Keizer now present a model of LFA-1-mediated lymphocyte adhesion, showing that LFA-1-dependent cell adhesion is a dynamic process in which ligand-binding affinity is regulated by intramolecular changes in LFA-1. This process is controlled by other lymphocyte surface structures, notably CD2 and CD3.

Activation of LFA-1: Role of Cations

Several observations indicate that the affinity of integrin receptors for their ligands can be modulated. Resting leukocytes or platelets do not adhere spontaneously, but a variety of stimuli can induce β1- (VLA-4, VLA-5, VLA-6), β2- (LFA-1, CR3), and β3-integrin (IIb/IIIa)-mediated cell-cell interactions. Exposure of lymphocytes, myeloid cells, or platelets to phorbol ester (PMA) strongly induces cell aggregation (1,2). Similarly, FMLP can stimulate CR3-mediated adhesion of granulocytes to endothelial cells (3,4) and activation of platelets by thrombin or ADP causes IIb/IIIa-mediated aggregation (5). A prominent characteristic in all these observations is that adhesion is induced without an apparent increase in receptor expression. This suggests that changes in affinity of the receptor for its ligand, or changes in the avidity (for instance, by alteration of the organization of the adhesion receptors at the cell surface), directly affect cell adhesion. Second messengers play a pivotal role in integrin activation, although at present the precise intracellular circuits that regulate integrin-mediated cell adhesion are not completely understood.

Activation of Lfa-1: The L16 Epitope is a Cation-Binding Reporter

Several observations indicate taht the affinity/avidity of integrin receptors for their ligands can be modulated. Resting leukocytes or platelets do not adhere spontaneously, but a variety of stimuli can induce β1- (VLA-4, VLA-5, VLA-6), β2- (LFA-1, CR3) and β3 integrin (IIb/IIIa) mediated cell-cell interactions. Exposure of lymphocytes, myeloid cells or platelets to phorbol ester (PMA) strongly includes cell aggregation (Rothlein and Springer, 1986; Patarroyo et al., 1985). Similarly, FMLP can stimulate CR3-mediated adhesion of granulocytes to endothelial celss (Buyon et al., 1988; Vedder and Harlan, 1988) and activation of platelets by thrombin or ADP causes IIb/IIIa mediated aggregation (Marguerie et al., 1979). A prominent characteristic in all these observations is that adhesion is induced without an apparent increase in receptor expression. This suggests that changes in the avidity (for instance by alteration of the organization of the adhesion receptors at the cell surface), directly affect cell adhesion. Second messengers play a pivotal role in integrin activation, although at present the precise intracellular circuits that regulate integrin mediated cell adhesion are not completely understood.