Association of tyrosine kinase p56lck with CD4 inhibits the induction of growth through the alpha beta T-cell receptor.
The membrane glycoprotein CD4 enhances antigen-mediated activation of T cells restricted by class II molecules of the major histocompatibility complex (MHC). This positive function has been attributed to the protein tyrosine kinase p56lck (ref. 4), which is noncovalently associated with the cytoplasmic portion of CD4, and is activated on CD4 aggregation. Antigen presentation by MHC class II molecules coaggregates CD4 and the T-cell antigen receptor (TCR alpha beta-CD3). Thus, the mutual specificity of CD4 and TCR alpha beta for the MHC-antigen complex results in the juxtaposition of p56lck and TCR alpha beta-CD3. In contrast, anti-CD4 antibodies can abrogate antigen-induced, as well as anti-TCR-induced T-cell activation, indicating that CD4 might also transduce negative signals. The molecular basis for this opposing function remains unclear. Here we show that the CD4-p56lck complex prohibits the induction of activation signals through the TCR-CD3 complex when not specifically included in the signalling process. This negative effect does not require anti-CD4 treatment, indicating that the induction of distinct negative signals is probably not involved. Rather, the results demonstrate that the CD4-p56lck complex provides prerequisite signals for antigen-receptor-induced T-cell growth and thus characterize a molecular mechanism for functional constraints imposed on T-cell activation by the MHC.
Haughn
L
L
Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada.
Gratton
S
S
Caron
L
L
Sékaly
R P
RP
Veillette
A
A
Julius
M
M
D000818:Animals; D015704:CD4 Antigens / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002999:Clone Cells; D004261:DNA Replication; D019868:Kanamycin Kinase; D008213:Lymphocyte Activation; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D046911:Macromolecular Substances; D051379:Mice; D010770:Phosphotransferases / Q000235:genetics / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011505:Protein-Tyrosine Kinases / Q000302:isolation & purification / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*; D014162:Transfection
D015704:CD4 Antigens; D046911:Macromolecular Substances; D011948:Receptors, Antigen, T-Cell; D010770:Phosphotransferases; D019868:Kanamycin Kinase; D011505:Protein-Tyrosine Kinases; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D002118:Calcium