Signals for activation of CD8-dependent adhesion and costimulation in CTLs.
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 upon 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 pathway, as neither increased production of inositol phosphates or mobilization of [Ca2+]i can be detected in response to the fluid-phase anti-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-regulating CD8 was confirmed by the inability of phorbol ester or calcium ionophore to substitute for TCR mAb in triggering adhesion to class I proteins. Instead, both phorbol ester and calcium ionophore inhibited the anti-TCR mAb-stimulated adhesion to class I. Inhibitors of protein tyrosine kinases also block TCR-activated, CD8-dependent adhesion to class I, and concomitantly block inositol phosphate release, Ca2+ mobilization 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 receptors 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 signaling events initiated by the TCR and propagated by CD8 and additional cell-surface receptors.
O'Rourke
A M
AM
Division of Membrane Biology, Medical Biology Institute, La Jolla, CA 92037.
Mescher
M F
MF
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D016827:CD8 Antigens / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D015550:Cell Degranulation; D002999:Clone Cells / Q000276:immunology; D006868:Hydrolysis; D015759:Ionomycin / Q000494:pharmacology; D007700:Kinetics; D008213:Lymphocyte Activation; D051379:Mice; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D016827:CD8 Antigens; D015815:Cell Adhesion Molecules; D018129:Phosphatidylinositol Phosphates; D011948:Receptors, Antigen, T-Cell; D015759:Ionomycin; D011505:Protein-Tyrosine Kinases; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium