Role of phosphoinositide 3-kinase in TCR-signaled regulation of CD8-mediated adhesion to class I MHC protein

CD8 must be activated by signaling through the TCR in order to mediate CTL adhesion. Up-regulation of adhesion to class I protein is shown to be blocked by specific inhibitors of phosphoinositide 3-OH kinase (P13-K), indicating a critical role for this enzyme in signaling or activation of CD8. A minimal TCR stimulus that activates CD8 does not result in a detectable increase in total cellular P13-K activity, but an increase in P13-K activity associated with P^59fyn kinase can be detected. Genistein blocks this increase concomitantly with blocking the activation of adhesion, suggesting that activation of fyn-associated P13-K is downstream of TCR-dependent activation of protein tyrosine kinase(s) in the signaling pathway that leads to up-regulation of CD8-dependent adhesion. Treatment of cells with phorbol ester also blocks the TCR-dependent increase in fyn-associated P13-K and inhibits CD8-dependent adhesion. This suggests a feedback model for deactivation of CD8 adhesion to allow target cell release by CTL and recycling to kill additional targets. In contrast, phorbol ester treatment up-regulates integrin-mediated adhesions, suggesting complex cross-talk between the TCR and the different adhesion/cosignaling receptors during the binding and killing of antigen-bearing targets.