β2-Integrin LFA-1 Signaling Through Phospholipase C-γ1 Activation

• Published in: Proceedings of the National Academy of Sciences - PNAS 1993-08, Vol.90 (15), p.7099-7103
• Main Authors: Kanner, Steven B., Grosmaire, Laura S., Ledbetter, Jeffrey A., Damle, Nitin K.
• Format: Article
• Language: English
• Subjects: Antibodies; Antigens; Biological and medical sciences; Blasts; Cell physiology; Crosslinking; Fundamental and applied biological sciences. Psychology; Integrins; Ligation; Molecular and cellular biology; Phosphorylation; Receptors; Signal transduction; T cell antigen receptors; T lymphocytes
• ISSN: 0027-8424; 1091-6490

One of the β2-integrins found on hematopoietic cells is lymphocyte function-associated antigen 1 (LFA-1), alymphocyte/myeloid cell-specific receptor that binds to members of the intercellular adhesion molecule (ICAM) family on antigen-presenting cells. Stimulation of LFA-1 with 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 phospholipase C-γ 1 (PLC-γ 1). Integrin β-chain (CD18) crosslinking independently induced downstream mobilization of intracellular Ca2+and potently costimulated TCR-induced Ca2+flux with an increase in both amplitude and kinetics. β2-Integrin signaling through this pathway was completely inhibited by herbimycin A and was prevented by TCR modulation. Coligation of the TCR via antibody and LFA-1 with a counter-receptor in the form of a soluble ICAM-1/Rg fusion protein resulted in prolonged tyrosine phosphorylation of PLC-γ 1. Monoclonal antibodies to both the α chain (CD11a) and the β chain (CD18) of LFA-1 induced Ca2+mobilization to different levels, suggesting epitope specificity for activation potential. In addition to PLC-γ 1, tyrosine phosphorylation of an 80-kDa protein substrate was augmented following CD18 crosslinking but was not TCR-dependent. The β2-integrin LFA-1 on T cells is therefore directly linked to a tyrosine kinase pathway that stimulates signaling by phosphatidylinositol-specific PLC-γ 1.