Cytotoxic T lymphocyte-induced loss of target cell adhesion and lysis involve common and separate signaling pathways

Recently, we demonstrated that an early event in the CTL-target cell (TC) interaction is loss of TC adherence to substrate. This loss of adhesion is Ag-specific, but distinct from the lytic event because it can ensue in nominally Ca2+-free medium. In this study, we examine further the mechanism of CTL-induced loss of adhesion, concentrating mainly on the signal transduction pathway. Based on the differential sensitivity of CTL to extracellular Ca2+, protein kinase C activation/depletion and inhibition by anti-Lyt-2 (CD8) or anti-CTL receptor (TCR) reagents, we demonstrate that CTL-induced loss of adhesion can be initiated through multiple activation pathways. Although CTL-mediated lysis is restricted to a Ca2+ and protein kinase C-dependent signaling mechanism, CTL-induced loss of adhesion is initiated in the presence or absence of extracellular Ca2+ or functional protein kinase C activity. Furthermore, although under physiologic conditions, anti-CD8 or anti-TCR reagents strongly block both CTL activities, under non-lytic conditions, they fail to inhibit the ability of CTL to promote loss of adhesion. These findings implicate the participation of additional CTL-TC ligand interactions resulting in loss of adhesion, and thus, provide further evidence to support the hypothesis that CTL-induced loss of adhesion can be initiated through multiple triggering pathways.