Regulation of the development of perforin-dependent cytotoxicity in CD4+ T cells by CD8+ T cells

Recent data has led to increased interest Jn understanding the role of CD4+ CTL and their mechanism of killing. We found that after depletion of CD&+ T cells, C/?4+ T cells in short-term in vitro mixed lymphocyte cultures developed strong antigen specific cytotoxic activity. Such CD4+ CTL lysed both Fas+ and FUA~ target cells and developed in Fas ligand-deficient gld mice but not in perform knockout mice, indicating that their cytotoxJc activity was primarily dependent on a perforin-based mechanism. The ability of CD8+ cells to inhibit the development of cytotoxic activity in CD4+ cells required activation and cell contact or very close proximity with the CD4+ cells. The CDS+ cells only inhibited development of perforin-utilizing CD4+ CTL and had no effect on CD4+ T cells that killed by a Fas ligand-dependent mechanism. Interestingly, while development of CD4f CTL from C57BL/6 mice was inhibited, a similar regulatory effect was not observed in C3H T cells. However, T cells from Fl animals displayed the phenotype of the B6 parent, establishing a genetic basis for the regulatory effect. Utilization of the FasFas ligand pathway by CD4+ CTL has been shown to be important in the maintenance of peripheral tolerance, but to have a minimal role in protection against viral and bacterial pathogens. Thus, the regulated existence of a population of CD4+ CTL that utilize perforin emphasizes the likely importance of these cells in a defensive role against pathogens, perhaps when a CD8+ cell response is absent.