PERFORIN-DEPENDENT CYTOTOXIC ACTIVITY AND LYMPHOKINE SECRETION BY CD4(-CELLS ARE REGULATED BY CD8(+) T-CELLS() T)

Factors influencing the development of CD4(+) T cell subpopulations wi th differing lymphokine profiles are well established. However, CD4(+) cells can show both perforin-and Fas ligand-dependent cytotoxicity, a nd little is known about conditions favoring the development of these effector activities. We now report that CD8(+) cells regulate the deve lopment of perforin-dependent cytotoxicity in CD4(+) cells. CD4(+) cel ls activated in either the presence or absence of CD8(+) cells develop ed Fas ligand-dependent cytotoxic activity, However, CD4(+) cells deve loped perforin-dependent cytotoxicity only in the absence of activated CD8(+) cells. CD8(+) cells also inhibited the development of IL-4-sec reting CD4(+) cells; however, there was no correlation between the exp ression of perforin-dependent cytotoxic activity and the ability to se crete IL-4, and perforin-dependent cytotoxic CD4(+) cells represented only 10% of isolated clones. This suggests that the two characteristic s 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 consist ent with mediation by IFN-gamma, but only when delivered at high conce ntrations requiring close proximity of the cells. In contrast, regulat ion of perforin-dependent cytotoxic activity of CD4(+) cells by CD8(+) cells seemed inconsistent with an IFN-gamma-dependent mechanism, sugg esting either direct cell contact or close proximity to allow delivery of an unidentified soluble factor, The characteristics of perforin-de pendent CD4(+) CTL and their regulation by activated CD8(+) cells sugg est that they represent a previously unrecognized subpopulation that p lays a defensive role when a CD8(+) cell response is absent.