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 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.
Jensen
P L
PL
Center of Immunology, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
Mescher
M F
MF
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D016827:CD8 Antigens / Q000502:physiology*; D002448:Cell Adhesion; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D015395:Histocompatibility Antigens Class I / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051076:Proto-Oncogene Proteins c-fyn; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D016827:CD8 Antigens; D015395:Histocompatibility Antigens Class I; D011518:Proto-Oncogene Proteins; D011948:Receptors, Antigen, T-Cell; D019869:Phosphatidylinositol 3-Kinases; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; D013755:Tetradecanoylphorbol Acetate