INCREASE IN THE SPECIFIC ACTIVITY OF P50(CSK) IN PROLIFERATING T-CELLS CORRELATES WITH DECREASED SPECIFIC ACTIVITY OF P56(LCK) AND P59(FYN)AND REDUCED PHOSPHORYLATION OF CD3 SUBUNITS

Depending on their prior antigen recognition history, mature T cells r espond with different functional outcomes to T cell receptor (TCR) sti mulation. These functional outcomes include proliferation, anergy and cell death. The biochemical basis underlying differential responses by mature T cells at different stages of their developmental pathway to TCR stimulation remains to be determined. We have previously shown tha t proliferating but not naive T cells were susceptible to apoptosis af ter TCR stimulation and that the tyrosine phosphorylation of TCR zeta, CD3 gamma, and CD3 epsilon in proliferating T cells was decreased aft er TCR stimulation. In this study, we determined whether differences i n phosphorylation between naive and proliferating T cells were due to altered regulation of p56(lck) (Lck) or p59(fyn) (Fyn) by their positi ve or negative regulators, CD45 or p50(csk) (Csk), respectively. We fo und that Lck was expressed at the same level and had the same phosphot yrosine content in naive and proliferating T cells. However, its autop hosphorylation activity was lower in proliferating cells, correspondin g to a 2-fold decrease in its specific kinase activity. Similarly, the specific kinase activity of Fyn was also decreased by about 2-fold in proliferating T cells. In contrast, although Csk was expressed at the same level in both cell types its specific kinase activity was increa sed by B-fold in proliferating T cells. The tyrosine phosphatase CD45, a positive regulator of sie-family kinases, was overexpressed by 3- t o 6-fold in proliferating cells. However, the specific activity of CD4 5 in naive and proliferating T cells was the same. Therefore, although the protein expression level of CD45 was increased in proliferating T cells it only partially compensated for the hyperactivity of Csk resu lting in a 2-fold reduction in the specific activity of Lck and Fyn in proliferating T cells. Copyright (C) 1996 Elsevier Science Ltd.