THE ROLE OF P56(LCK) IN CD4-MEDIATED SUPPRESSION OF CD3-INDUCED EARLYSIGNALING EVENTS IN T-LYMPHOCYTES

Crosslinking of the CD4 coreceptor can inhibit subsequent T-cell activ ation via the T-cell antigen receptor (TCR)/CD3 complex. The ability o f the human immunodeficiency virus (HIV) envelope protein, gp120, to c ause similar inhibition has implicated this inhibitory signal in the i nduction of T-cell anergy and apoptosis observed in the acquired immun odeficiency syndrome (AIDS). in order to clarify the biochemical basis of this inhibition, we analyzed the effect of CD4 ligation on early s ignaling events induced by subsequent CD3xCD4 co-crosslinking. By comp arison with CD3 crosslinking alone, CD3xCD4 co-crosslinking of a CD3()CD4(+) human T-cell leukemia line (SupT1) resulted in an enhanced inc rease in free intracellular calcium concentration and tyrosine phospho rylation of several cellular substrates, including the prominent phosp horylation of an unidentified 120-kDa protein (p120). Prior CD4 ligati on inhibited these responses. Similar results were obtained with A3.01 , another CD3(+)CD4(+) T leukemic line. However, p120 was only minor p hosporylated on tyrosine upon receptor crosslinking in A2.01/CD4(-cyt4 01), a derivative line expressing a truncated CD4 coreceptor lacking i ts cytoplasmic domain which binds the p56(lck) protein tyrosine kinase (PTK). Furthermore, prior CD4 ligation failed to inhibit in this line the increased tyrosine phosphorylation induced by subsequent CD3xCD4 co-crosslinking. Thus, prior CD4 crosslinking, or expression of trunca ted CD4, are both associated with reduced p120 phosphorylation. These results suggest