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Two pathways of exocytosis of cytoplasmic granule contents and target cell
killing by cytokine-induced CD3+ CD56+ killer cells
BA Mehta, IG Schmidt-Wolf, IL Weissman and RS Negrin
Department of Medicine, Stanford University Medical Center, CA, USA.
Cytokine-induced killer (CIK) cells are non-major histocompatibility
complex-restricted cytotoxic cells generated by incubation of peripheral
blood lymphocytes with anti-CD3 monoclonal antibody (MoAb), interleukin-2
(IL-2), IL-1, and interferon-gamma. Cells with the greatest effector
function in CIK cultures coexpress CD3 and CD56 surface molecules. CIK cell
cytotoxicity can be blocked by MoAbs directed against the cell surface
protein leukocyte function associated antigen-1 but not by anti-CD3 MoAbs.
CIK cells undergo release of cytoplasmic cytotoxic granule contents to the
extracellular space upon stimulation with anti-CD3 MoAbs or susceptible
target cells. Maximal granule release was observed from the CD3+ CD56+
subset of effector cells. The cytoplasmic granule contents are lytic to
target cells. Treatment of the effector cells with a cell-permeable analog
of cyclic adenosine monophosphate (cAMP) inhibited anti-CD3 MoAb and target
cell- induced degranulation and cytotoxicity of CIK cells. The
immunosuppressive drugs cyclosporin (CsA) and FK506 inhibited anti-CD3-
mediated degranulation, but did not affect cytotoxicity of CIK cells
against tumor target cells. In addition, degranulation induced by target
cells was unaffected by CsA and FK506. Our results indicate that two
mechanisms of cytoplasmic granule release are operative in the CD3+ CD56+
killer cells; however, cytotoxicity proceeds through a cAMP- sensitive,
CsA- and FK506-insensitive pathway triggered by yet-to-be- identified
target cell surface molecules.
Volume 86,
Issue 9,
pp. 3493-3499,
11/01/1995
Copyright © 1995 by The American Society of Hematology
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