Protein tyrosine kinase p56-Lck regulates lymphocyte function-associated 1 adhesion molecule expression, granule exocytosis, and cytolytic effector function in a cloned T cell.

Academic Article

Abstract

  • Elevated levels of p56-Lck kinase activity were achieved in an interleukin 2 (IL-2)-dependent cloned cytolytic T cell CTLL-2 through gene transfer approaches. CTLL-2-Lck cells remained dependent on IL-2 for growth and survival in culture but exhibited markedly elevated, IL-2-independent cytolytic activity against a variety of tumor targets. This immune cell effector function was similar to the non-major histocompatibility complex-restricted cytolytic activity previously described for lymphokine activated killer (LAK) cells, and involved a cytolytic mechanism that was independent of protein synthesis in either the T cells or the tumor targets. Characterization of CTLL-2-Lck cells revealed markedly elevated levels of both the alpha (CD11a) and beta (CD18) chains of the cell adhesion molecule lymphocyte function-associated 1 (LFA-1) and increased binding of these T cells to a recombinant protein representing the extracellular domain of the LFA-ligand, intercellular adhesion molecule 1 (ICAM-1). Antibodies to CD11a partially abrogated cytolytic killing of tumor target cells by CTLL-2-Lck cells, suggesting that the upregulation in LFA protein levels potentially accounts at least in part for the phenotype of these T cells. Gene transfer-mediated elevations in p56-Lck kinase activity in an IL-3-dependent myeloid cell clone 32D.3 also resulted in increased LFA-1 expression, demonstrating that the findings are not unique to CTLL-2 cells. In addition to upregulation of LFA-1 expression, CTLL-Lck cells also exhibited more efficient exocytosis of cytotoxic granules upon activation with Ca(2+)-ionophore and phorbol ester, relative to control transfected and untransfected CTLL-2 cells. The findings functionally link the Lck kinase to a T cell effector pathway involved in cell-mediated cytotoxicity.
  • Published In

    Keywords

  • Cell Adhesion, Cell Adhesion Molecules, Cells, Cultured, Clone Cells, Cytoplasmic Granules, Cytotoxicity, Immunologic, Exocytosis, Glucuronidase, Humans, Intercellular Adhesion Molecule-1, Lymphocyte Function-Associated Antigen-1, Lymphocyte Specific Protein Tyrosine Kinase p56(lck), Protein-Tyrosine Kinases, T-Lymphocytes, Transfection
  • Digital Object Identifier (doi)

    Author List

  • Torigoe T; Millan JA; Chan KW; Taichman R; Brian AA; Reed JC; Tachman R [corrected to Taichman R
  • Start Page

  • 1115
  • End Page

  • 1127
  • Volume

  • 180
  • Issue

  • 3