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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.

Proceedings of the National Academy of Sciences of the United States of America
|August 1, 1993
PubMed

Insights

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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