Activation-induced cell death in proliferating T cells is associated with altered tyrosine phosphorylation of TCR/CD3 subunits.

The first signaling event that occurs after stimulation of the TCR is an increase in the tyrosine phosphorylation of a number of proteins including the TCR-zeta chain and CD3 subunits. It is known that proliferating T cells respond differently to TCR stimulation when compared with naive T cells. Stimulation of the TCR on proliferating T cells has been shown to result in cell death by apoptosis, a process referred to as activation-induced cell death (AICD). In this study we have determined the pattern of tyrosine phosphorylation of TCR-zeta and the CD3 subunits of naive and proliferating CD4- CD8+ T cells that express a transgenic TCR that is specific for the male Ag presented by Db class I molecules after TCR stimulation. AICD in proliferating T cells was mediated by stimulation with anti-TCR/CD3, but not anti-Thy-1, anti-CD8, or anti-Db mAbs. When compared with naive T cells, tyrosine phosphorylation of TCR-zeta was dramatically decreased in proliferating cells. Furthermore, whereas CD3 delta, CD3 epsilon, and CD3 gamma of naive T cells were phosphorylated in a 1:2:1 ratio after TCR stimulation, these subunits in proliferating T cells were tyrosine phosphorylated in a 1:1:0 ratio after TCR stimulation. Altered phosphorylation of these subunits was not caused by the lack of synthesis or amount of these proteins in proliferating cells. This is the first study implicating altered tyrosine phosphorylation of TCR/CD3 subunits in AICD.