Identification of a population of CD4⁺ CTL that utilizes a perforin- rather than a Fas ligand-dependent cytotoxic mechanism

Although cytotoxic activity has generally been shown to reside in the CD8⁺ population of T lymphocytes, there are numerous examples of cytotoxic CD4⁺ T cells. In the present study, we found that after depletion of CD8⁺ T cells, CD4⁺ T cells cultured in short-term in vitro mixed lymphocyte cultures developed strong Ag-specific cytotoxic activity. Such CD4⁺ CTL lysed both Fas⁺ and Fas^- target cells and developed in Fas ligand-deficient gld mice. Thus, in contrast to several recent reports involving long-term T cell clones or short-term mitogen-activated splenocytes, the cytotoxic activity of these CD4⁺ CTL is not dependent on Fas-Fas ligand interactions. However, CD4⁺ cells derived in a similar manner from perforin knockout mice showed greatly decreased target cell lysis, indicating that their cytotoxic activity is primarily dependent on a perforin-based mechanism. The Fas-Fas ligand pathway 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 existence of a population of CD4⁺ CTL that utilizes perforin re-emphasizes the likely importance of these cells in a classical defensive role against foreign pathogens, in addition to their already implied role as modulators of the immune response.