Aging Increases CD8 T Cell Apoptosis Induced by Hyperstimulation but Decreases Apoptosis Induced by Agonist Withdrawal in Mice

Apoptosis of T cells is thought to play a critical role in intrathymic T cell selection, in controlling the strength of the immune response to antigens, and in peripheral modulation of the T cell repertoire by influencing memory cell formation and survival. Peripheral T lymphocyte apoptosis or activation-induced cell death can be inducedin vitroby repeated stimulation through the T cell receptor (TCR), and several groups have reported that aging increases the susceptibility of T cells to hyperstimulation-induced cell death in mice and humans. Alternately, apoptosis can also be induced in T cells by withdrawal of TCR stimulation from T cell blasts late in the activation process. This agonist withdrawal cell death, unlike apoptosis induced by repeated stimulation, is Fas- and TNFα-independent but is modulated by CD30 ligation. We show here that aging leads to an increase in susceptibility to apoptosis induced by repeated stimulation, but also to a decline in mouse CD8 T cell sensitivity to apoptosis induced by agonist withdrawal. Cell mixture experiments show that intercellular signals are required for the induction of apoptosis after agonist withdrawal and that the CD8 cells from aged mice can respond to these death-inducing signals but cannot produce them. A defect in this form of apoptosis after cessation of TCR signaling might contribute to the accumulation of functionally ineffective CD8 cells in aging mice.