Distinct roles for CD4 and CD8 as co-receptors in T cell receptor signalling.

We demonstrate that CD4 and CD8 modify signals induced through the T cell receptor for antigen (TCR alpha beta) in distinct fashions. Pretreatment of CD4+ lymph node T cells with CD4-specific monoclonal antibody results in a tenfold inhibition of DNA synthesis induced by anti-TCR alpha beta. In contrast, pretreatment of CD8+ T cells with CD8-specific mAb has no effect on DNA synthesis subsequently induced through TCR alpha beta. While inhibiting late activation signals, pretreatment with anti-CD4 does not detectably alter the pattern of anti-TCR alpha beta-induced tyrosine phosphorylation of cellular proteins, nor subsequent Ca2+ mobilization. The distinct biological consequences of anti-CD4 and anti-CD8 pretreatment correlate with the differential association of their respective ligands with the cellular protein tyrosine kinase, p56lck. While both T cell lineages contain similar levels of cellular p56lck, tenfold more is associated with CD4 than with CD8. This difference is associated with the differential effects of pretreatment with anti-CD4 and anti-CD8 on the distribution and activity of p56lck. Further, antibody-mediated aggregation of TCR alpha beta on CD4+ T cells induces the appearance of a p56lck species with decreased mobility in sodium dodecylsulfate-polyacrylamide gel electrophoresis. This effect is observed in CD4+ T cells exclusively and involves the fraction of p56lck which is not associated with CD4. The results presented here demonstrate that the signalling elements which couple the antigen receptor to second messenger-generating systems are under distinct physical and/or functional constraints in the two T cell lineages.