Interplay between cell division and cell death during TCR triggering

Cell death is crucial to avoid excessive T cell expansion. During primary T cell expansion in response to pathogen or after vaccination, the amount of foreign Ag determines the degree of clonal amplification and death. Here, we studied the balance between cell proliferation and death, as well as susceptibility to cell death, during TCR triggering. After priming of CD4 T cells from AND-TCR (Vbeta3, Valpha11)-transgenic mice with a high dose of pigeon cytochrome c peptide 88-104, the cell expansion rate was significantly reduced by marked clonal elimination compared to lower Ag doses, whereas the number of cell divisions reached was similar at all Ag doses. TCR re-engagement on activated T cells induced cell death, irrespective of the dose of Ag encountered during primary stimulation. Surprisingly, commitment to apoptosis occurred as early as the first division on all dividing cells both in vitro and in vivo. This phenomenon was highly selective, as activated but non-dividing cells did not undergo cell death, whereas cells that had divided once became susceptible to cell death. These findings have direct implications for the peripheral homeostatic mechanism following Ag challenge and for designing primary/booster vaccine strategies.