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 (PI3‐K), indicating a critical role for this enzyme in signaling for activation of CD8. A minimal TCR stimulus that activates CD8 does not result in a detectable increase in total cellular PI3‐K activity, but an increase in PI3‐K activity associated with p59fyn kinase can be detected. Genistein blocks this increase concomitantly with blocking the activation of adhesion, suggesting that activation of fyn‐associated PI3‐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 PI3‐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.