Perforin-dependent cytotoxic activity and lymphokine secretion by CD4⁺ T cells are regulated by CD8⁺ T cells

Factors influencing the development of CD4⁺ T cell subpopulations with differing lymphokine profiles are well established. However, CD4⁺ cells can show both perforin- and Fas ligand-dependent cytotoxicity, and little is known about conditions favoring the development of these effector activities. We now report that CD8⁺ cells regulate the development of perforin-dependent cytotoxicity in CD4⁺ cells. CD4⁺ cells activated in either the presence or absence of CD8⁺ cells developed Fas ligand-dependent cytotoxic activity. However, CD4⁺ cells developed perforin-dependent cytotoxicity only in the absence of activated CD8⁺ cells. CD8⁺ cells also inhibited the development of IL-4-secreting CD4⁺ cells; however, there was no correlation between the expression of perforin-dependent cytotoxic activity and the ability to secrete IL-4, and perforin-dependent cytotoxic CD4⁺ cells represented only 10% of isolated clones. This suggests that the two characteristics are expressed in different CD4⁺ subsets and might be regulated by distinct effects of the CD8⁺ cells. In keeping with this, regulation of the lymphokine profile of CD4⁺ cells by CD8⁺ cells was consistent with mediation by IFN-γ, but only when delivered at high concentrations requiring close proximity of the cells. In contrast, regulation of perforin-dependent cytotoxic activity of CD4⁺ cells by CD8⁺ cells seemed inconsistent with an IFN-γ-dependent mechanism, suggesting either direct cell contact or close proximity to allow delivery of an unidentified soluble factor. The characteristics of perforin-dependent CD4⁺ CTL and their regulation by activated CD8⁺ cells suggest that they represent a previously unrecognized subpopulation that plays a defensive role when a CD8⁺ cell response is absent.