ROLE OF EXTRACELLULAR ADENOSINE-TRIPHOSPHATE IN THE CYTOTOXIC T-LYMPHOCYTE-MEDIATED LYSIS OF ANTIGEN-PRESENTING CELLS

The lysis of antigen presenting cells (APCs) by cytotoxic T lymphocyte s (CTLs) may be one mechanism whereby an immune response is downregula ted by Staphylococcus superantigens. Disappearance of monocytes/macrop hages from staphylococcal enterotoxin A (SEA)-activated peripheral blo od mononuclear cell (PBMC) cultures, but not from control PBMC culture s was seen by flow cytometry, Recently, adenosine triphosphate (ATP) h as been described as an effector molecule in CTL-mediated lysis of som e murine tumor target cells. We have also shown that ATP caused the ly sis 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 pla y 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 S EA-pulsed macrophages, while control, unpulsed, macrophages were unaff ected, The addition of hexokinase, an enzyme that hydrolyzes ATP, sign ificantly 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 i s released from CTLs during antigen presentation, and that IFN gamma-a ctivated macrophages, which are inherently more sensitive to this medi ator, are readily lysed and therefore removed from circulation, thus d ownregulating an immune response. (C) 1995 by The American Society of Hematology.