CONTRIBUTION OF TYROSINE KINASES TO THE SELECTIVE ORIENTATION OF HUMAN CD4(-CELLS TOWARD PROLIFERATION OR CYTOLYTIC FUNCTION() BIFUNCTIONALCLONED T)

We show that T cell activation of human CD4(+) cloned T cells through the CD2 molecule can induce either autocrine proliferation or cytolysi s, depending on the pair of anti-CD2 mAbs used for stimulation, that i s, D66/T11(1) or GT2/T11(1), respectively. As the earliest biochemical event after CD2 stimulation is likely the induction of tyrosine phosp horylation of various proteins, we investigated whether differential a ctivation of protein tyrosine kinases (PTKs) could contribute to the s elective induction of each function. Results show that herbimycin A, a potent PTK inhibitor, markedly decreased the induction of both prolif eration and cytolysis. This implies a regulatory role for tyrosine pho sphorylation in the induction of each function by CD2. However, that P TKs are differentially activated upon induction of proliferation by D6 6/T11(1) or cytotoxic function by GT2/T11(1) emanated from two differe nt approaches. First, immunoblotting total cellular extracts with an a nti-phosphotyrosine mAb showed different patterns of tyrosine phosphor ylation depending on the pair of CD2 mAbs used for stimulation. Second , a differential activation of p56(lck), a src-related PTK, was observ ed after stimulation with D66/T11(1) and GT2/T11(1). Although inductio n of proliferation by D66/T11(1) was correlated with increased Lck act ivity, this was not observed when cells were triggered to lyse by GT2/ T11(1). Thus, by providing striking correlative evidences linking diff erences in PTK activation with induction of different functions in bif unctional cloned T cells, our results strongly suggest that PTKs may c ontribute to the selective orientation of T cell functions at a single -cell level.