Association of tyrosine kinase p56^lck with CD4 inhibits the induction of growth through the αβ T-cell receptor

Abstract

THE membrane glycoprotein CD4 enhances antigen-mediated activation of T cells restricted by class II molecules of the major histocompatibility complex (MHC)^1–3. This positive function has been attributed to the protein tyrosine kinase p56^lck (ref. 4), which is noncovalently associated with the cytoplasmic portion of CD4^5,6, and is activated on CD4 aggregation⁷. Antigen presentation by MHC class II molecules coaggregates CD4 and the T-cell antigen receptor (TCRαβ–CD3)⁸. Thus, the mutual specificity of CD4 and TCRαβ for the MHC–antigen complex results in the juxtaposition of p56^lck and TCRαβ–CD3^9–13. In contrast, anti-CD4 antibodies can abrogate antigen-induced^14–17, as well as anti-TCR-induced^18–20 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–p56^lck 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–p56^lck 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.