Cytotoxic T-lymphocyte activation involves a cascade of signalling and adhesion events.
In addition to the antigen-specific T-cell receptor (TCR), T cells bear an array of 'accessory' molecules that can contribute to stable adhesion to the antigen-bearing cell and provide costimulatory signals. For several of these, T-cell adhesion to the ligand can be activated by TCR-dependent signalling (a signal from the TCR primes the coreceptor to bind to its ligand). It is unclear whether the individual coreceptors share common mechanisms of priming and cosignalling, and perhaps act in a redundant manner, or whether they act in a distinct way and contribute uniquely to the activation process. We report here the use of isolated alloantigen, class I proteins and fibronectin ligands to show that coreceptors on cytotoxic T lymphocytes are activated sequentially and deliver distinct biochemical signals on binding to their ligands. TCR engagement activates CD8 by a protein tyrosine kinase-dependent pathway, and CD8 then acts as a signal for initiation of polyphosphoinositide hydrolysis on binding to class I. In contrast, activated adhesion to fibronectin does not initiate polyphosphoinositide hydrolysis, but amplifies hydrolysis once it has been initiated. Thus, cytotoxic T-lymphocyte activation involves a TCR-initiated cascade of adhesion and signalling events leading to response.
O'Rourke
A M
AM
Division of Membrane Biology, Medical Biology Institute, La Jolla, California 92037.
Mescher
M F
MF
D016227:Benzoquinones; D015704:CD4 Antigens / Q000502:physiology; D016827:CD8 Antigens / Q000502:physiology; D002448:Cell Adhesion; D002999:Clone Cells; D004261:DNA Replication / Q000187:drug effects; D019833:Genistein; D006801:Humans; D007294:Inositol / Q000378:metabolism; D007295:Inositol Phosphates / Q000378:metabolism*; D007529:Isoflavones / Q000494:pharmacology; D047029:Lactams, Macrocyclic; D008213:Lymphocyte Activation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011809:Quinones / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D017828:Rifabutin / Q000031:analogs & derivatives; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000502:physiology
D016227:Benzoquinones; D015704:CD4 Antigens; D016827:CD8 Antigens; D007295:Inositol Phosphates; D007529:Isoflavones; D047029:Lactams, Macrocyclic; D011809:Quinones; D011948:Receptors, Antigen, T-Cell; D017828:Rifabutin; D007294:Inositol; C020754:herbimycin; D019833:Genistein; D011505:Protein-Tyrosine Kinases