Homeostatic regulation of CD8(+) T cells by perforin

To prevent uncontrolled expansion, the massive proliferation of T cells dur ing an acute immune response has to be followed by controlled deletion. Her e we show that similar to Fas, perforin is not only an important effector m olecule of cytotoxic T lymphocytes (CTL) but also involved in down-regulati ng peripheral T cells. Mice deficient for both the CTL effector molecule pe rforin and the apoptosis-inducing Pas ligand spontaneously develop infiltra tion of highly activated CD8(+) T cells in kidney and liver and die between 5 and 12 weeks of age. Injection of staphylococcal enterotoxin B (SEB) int o perforin-deficient mice results in dramatically increased selective expan sion and prolonged persistence of CD8(+), but not CD4(+), SEE-reactive T ce lls. Also, secondary immunization of TCR transgenic perforin-deficient mice with the lymphocytic choriomeningitis virus glycoprotein-derived epitope p eptide leads to an increased proliferation of transgenic CD8(+) T cells, th at is not explained by failure to deplete professional antigen-presenting c ells. These results point to a novel mechanism of T cell homeostasis in whi ch the acquisition of perforin-dependent cytotoxic activity regulates the e xpansion and persistence of CD8(+) effector T cells in vivo.