Jensen P L, Mescher M F
Center of Immunology, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
Eur J Immunol. 2001 Dec;31(12):3612-21. doi: 10.1002/1521-4141(200112)31:12<3612::aid-immu3612>3.0.co;2-j.
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 p59(fyn) 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.
