BETA-2-INTEGRIN LFA-1 SIGNALING THROUGH PHOSPHOLIPASE C-GAMMA-1 ACTIVATION

One of the beta2-integrins found on hematopoietic cells is lymphocyte function-associated antigen 1 (LFA-1), a lymphocyte/myeloid cell-speci fic receptor that binds to members of the intercellular adhesion molec ule (ICAM) family on antigen-presenting cells. Stimulation of LFA-1 wi th antibodies or purified ICAMs induces augmentation of T-cell antigen receptor (TCR)-directed T-cell responsiveness. In the present study, LFA-1 was shown to be linked to the tyrosine kinase signaling pathway that stimulates tyrosine phosphorylation and activation of phospholipa se C-gamma1 (PLC-gamma1). Integrin beta-chain (CD18) crosslinking inde pendently induced down-stream mobilization of intracellular Ca2+ and p otently costimulated TCR-induced Ca2+ flux with an increase in both am plitude and kinetics. Beta2-integrin signaling through this pathway wa s completely inhibited by herbimycin A and was prevented by TCR modula tion. Coligation of the TCR via antibody and LFA-1 with a counter-rece ptor in the form of a soluble ICAM-1/Rg fusion protein resulted in pro longed tyrosine phosphorylation of PLC-gamma1. Monoclonal antibodies t o both the alpha chain (CD11a) and the beta chain (CD18) of LFA-1 indu ced Ca2+ mobilization to different levels, suggesting epitope specific ity for activation potential. In addition to PLC-gamma1, tyrosine phos phorylation of an 80-kDa protein substrate was augmented following CD1 8 crosslinking but was not TCR-dependent. The beta2-integrin LFA-1 on T cells is therefore directly linked to a tyrosine kinase pathway that stimulates signaling by phosphatidylinositol-specific PLC-gamma1.