SIGNALS FOR ACTIVATION OF CD8-DEPENDENT ADHESION AND COSTIMULATION INCTLS

Adhesion of CD8(+) CTL to purified class I proteins has been shown to be regulated by the TCR: nonactivated CTL do not adhere to immobilized class I proteins (non-Ag), but adhesion becomes readily detectable up on treatment of the CTL with fluid-phase anti-TCR mAb. Signals for up- regulating CD8 adhesion do not appear to involve products of the PI pa thway, as neither increased production of inositol phosphates or mobil ization of [Ca2+](i) can be detected in response to the fluid-phase an ti-TCR mAb, but both occur when the CTL then bind to class I protein. The lack of a role for phosphoinositide pathway products in up-regulat ing CD8 was confirmed by the inability of phorbol ester or calcium ion ophore to substitute for TCR mAb in triggering adhesion to class I pro teins. Instead, both phorbol ester and calcium ionophore inhibited the anti-TCR mAb-stimulated adhesion to class I. Inhibitors of protein ty rosine kinases also block TCR-activated, CD8-dependent adhesion to cla ss I, and concomitantly block inositol phosphate release, Ca2+ mobiliz ation and degranulation. Inhibition of signaling and response does not appear to be caused solely by the inhibition of adhesion to class I, however, because these inhibitors also block signaling in response to immobilized anti-TCR mAb under conditions in which binding of other re ceptors to their ligands is not necessary to initiate phosphoinositide hydrolysis and degranulation. These results lend further support for a model in which CTL activation involves a cascade of adhesion and sig naling events initiated by the TCR and propagated by CD8 and additiona l cell-surface receptors.