Antagonism of cytotoxic T-lymphocyte activation by soluble CD8.
The CD8 co-receptor is important in the differentiation and selection of class I MHC-restricted T cells during thymic development, and in the activation of mature T lymphocytes in response to antigen. Here we show that soluble CD8alphaalpha receptor, despite an extremely low affinity for MHC, inhibits activation of cytotoxic lymphocytes by obstructing CD3 zeta-chain phosphorylation. We propose a model for this effect that involves interference of productive receptor multimerization at the T-cell surface. These results provide new insights into the mechanism of T-cell activation and evidence that CD8 function is exquisitely sensitive to disruption, an effect that might be exploited by molecular therapeutics.
Sewell
A K
AK
Nuffield Department of Clinical Medicine, Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, UK.
Gerth
U C
UC
Price
D A
DA
Purbhoo
M A
MA
Boulter
J M
JM
Gao
G F
GF
Bell
J I
JI
Phillips
R E
RE
Jakobsen
B K
BK
D017252:CD3 Complex / Q000378:metabolism; D016827:CD8 Antigens / Q000276:immunology / Q000494:pharmacology*; D019281:Dimerization; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D008285:Major Histocompatibility Complex; D018448:Models, Immunological; D010455:Peptides / Q000276:immunology / Q000494:pharmacology; D010766:Phosphorylation; D011487:Protein Conformation; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015398:Signal Transduction; D012995:Solubility; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology
D017252:CD3 Complex; D016827:CD8 Antigens; D015395:Histocompatibility Antigens Class I; D008024:Ligands; D010455:Peptides; D011948:Receptors, Antigen, T-Cell