Homeostatic regulation of CD8+ T cells by perforin

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Abstract
To prevent uncontrolled expansion, the massive proliferation of T cells during an acute immune response has to be followed by controlled deletion. Here we show that similar to Fas, perforin is not only an important effector molecule of cytotoxic T lymphocytes (CTL) but also involved in down‐regulating peripheral T cells. Mice deficient for both the CTL effector molecule perforin and the apoptosis‐inducing Fas ligand spontaneously develop infiltration 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) into perforin‐deficient mice results in dramatically increased selective expansion and prolonged persistence of CD8+, but not CD4+, SEB‐reactive T cells. Also, secondary immunization of TCR transgenic perforin‐deficient mice with the lymphocytic choriomeningitis virus glycoprotein‐derived epitope peptide leads to an increased proliferation of transgenic CD8+ T cells, that is not explained by failure to deplete professional antigen‐presenting cells. These results point to a novel mechanism of T cell homeostasis in which the acquisition of perforin‐dependent cytotoxic activity regulates the expansion and persistence of CD8+ effector T cells in vivo.