Journal of Experimental Medicine, Vol 180, 1115-1127, Copyright © 1994 by Rockefeller University Press

ARTICLES

Protein tyrosine kinase p56-Lck regulates lymphocyte function- associated 1 adhesion molecule expression, granule exocytosis, and cytolytic effector function in a cloned T cell [published erratum appears in J Exp Med 1995 Jan 1;181(1):442]

T Torigoe, JA Millan, KW Chan, R Taichman, AA Brian, JC Reed and R] Tachman R [corrected to Taichman
La Jolla Cancer Research Foundation, Cancer Research Center, California 92037.

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.
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