IL-4 diminishes perforin-mediated and increases Fas ligand-mediated cytotoxicity in vivo

CTL have evolved two major mechanisms for target cell killing: one mediated by perforin/granzyme secretion and the other by Fas/Fas ligand (L) interaction, Although cytokines are integral to the development of naive CTL into cytolytic effecters, the role of cytokines on mechanisms of CTL killing is just emerging, In this study, we evaluate the effects of IL-4 in Fas(CD95)/ FasL(CD95L)-mediated killing of Fas-overexpressing target cells, Recombinant vaccinia viruses (vv) were constructed to express respiratory syncytial virus M2 Ag alone (vvM2) or coexpress M2 and IL-4 (vvM2/IL-4). MHC-matched Fas-overexpressing target cells (L1210Fas(+)) were used to measure both perforin- and Fast-mediated killing pathways. In contrast to Fas-deficient (L1210Fas(-)) target cells, effecters from vvM2/IL-4-immunized mice were able to lyse L1210Fas(+) target cells with similar magnitude as vvM2-infected mice. Addition of EGTA/Mg2+ revealed that effecters from vvM2/IL-4-infected mice primarily lyse targets by a Ca2+-independent Fas/FasL pathway. Analysis of Fast expression by flow cytometry showed that IL-4 increased cell surface Fast expression on CD4+ and CD8+ splenocytes, with peak expression on day 4 after infection. These data demonstrate that IL-4 increases Fast expression on T cells, resulting in a shift of the mechanism of CTL killing from a dominant perforin-mediated cytolytic pathway to a dominant Fast-mediated cytolytic pathway.