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Beta 2-integrin LFA-1 signaling through phospholipase C-gamma 1 activation
S B Kanner1, L S Grosmaire, J A Ledbetter
1Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, WA 98121.
Summary
Lymphocyte function-associated antigen 1 (LFA-1) on T cells links to a tyrosine kinase pathway, activating phospholipase C-gamma 1 (PLC-gamma 1) signaling. This pathway enhances T-cell receptor responses and calcium flux.
Area of Science:
- Immunology
- Cell Signaling
- Molecular Biology
Background:
- Lymphocyte function-associated antigen 1 (LFA-1) is a beta 2-integrin on hematopoietic cells.
- LFA-1 interacts with intercellular adhesion molecules (ICAMs) on antigen-presenting cells.
- LFA-1 stimulation augments T-cell receptor (TCR)-directed T-cell responsiveness.
Purpose of the Study:
- To investigate the signaling pathway linked to LFA-1.
- To determine LFA-1's role in tyrosine kinase activation and phospholipase C-gamma 1 (PLC-gamma 1) signaling.
- To elucidate LFA-1's contribution to T-cell activation.
Main Methods:
- Crosslinking of the integrin beta-chain (CD18) of LFA-1.
- Stimulation with soluble ICAM-1/Rg fusion protein.
- Inhibition studies using herbimycin A and TCR modulation.
- Analysis of tyrosine phosphorylation and intracellular Ca2+ mobilization.
Main Results:
- LFA-1 is linked to a tyrosine kinase pathway activating PLC-gamma 1.
- CD18 crosslinking independently induced Ca2+ mobilization and costimulated TCR-induced Ca2+ flux.
- TCR modulation prevented beta 2-integrin signaling, while herbimycin A completely inhibited it.
- Coligation of TCR and LFA-1 prolonged PLC-gamma 1 tyrosine phosphorylation.
- Epitope specificity was observed for LFA-1 chain activation potential.
- Tyrosine phosphorylation of an 80-kDa protein was augmented by CD18 crosslinking independently of TCR.
Conclusions:
- The beta 2-integrin LFA-1 on T cells is directly linked to a tyrosine kinase pathway.
- This pathway stimulates signaling by phosphatidylinositol-specific PLC-gamma 1.
- LFA-1 plays a crucial role in modulating T-cell activation and signaling.
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