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Role of extracellular adenosine triphosphate in the cytotoxic T-
lymphocyte-mediated lysis of antigen presenting cells
DK Blanchard, S Wei, C Duan, F Pericle, JI Diaz and JY Djeu
Department of Medical Microbiology and Immunology, University of South
Florida College of Medicine, Tampa, USA.
The lysis of antigen presenting cells (APCs) by cytotoxic T lymphocytes
(CTLs) may be one mechanism whereby an immune response is downregulated by
Staphylococcus superantigens. Disappearance of monocytes/macrophages from
staphylococcal enterotoxin A (SEA)-activated peripheral blood mononuclear
cell (PBMC) cultures, but not from control PBMC cultures was seen by flow
cytometry. Recently, adenosine triphosphate (ATP) has been described as an
effector molecule in CTL-mediated lysis of some murine tumor target cells.
We have also shown that ATP caused the lysis of human macrophages, and that
treatment of cells with interferon gamma (IFN gamma) rendered macrophages
significantly more sensitive to ATP than untreated cells. To show that this
purine nucleotide may play a role in modulating the immune system, we
generated human CTLs that were stimulated with SEA, and used them as
effector cells against SEA-pulsed autologous macrophages. CTLs were found
to specifically lyse SEA-pulsed macrophages, while control, unpulsed,
macrophages were unaffected. The addition of hexokinase, an enzyme that
hydrolyzes ATP, significantly abrogated the killing of SEA-pulsed cells
during the assay. In examining the mechanism of cytotoxicity, electron
microscopy showed that macrophages incubated with both ATP and CTLs
underwent necrosis, rather than apoptosis. From these results, it is
suggested that ATP is released from CTLs during antigen presentation, and
that IFN gamma- activated macrophages, which are inherently more sensitive
to this mediator, are readily lysed and therefore removed from circulation,
thus downregulating an immune response.
Volume 85,
Issue 11,
pp. 3173-3182,
06/01/1995
Copyright © 1995 by The American Society of Hematology
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