VIP and PACAP inhibit Fas ligand-mediated bystander lysis by CD4(+) T cells.

FasL/Fas-mediated lysis represents the major cytotoxic mechanism for CD4(+) effectors, with important consequences for immune cell homeostasis. Upon stimulation by specific antigen-presenting cells (APCs), CD4(+) effectors can lyse the cognate APCs (direct targets) and neighboring innocent bystanders. Previously we showed that the neuropeptides VIP and PACAP prevent FasL expression and activation-induced cell death in T cells. In this study we investigated the effects of VIP and PACAP on FasL expression and subsequent direct and bystander lysis by CD4(+) effectors generated in vivo. VIP/PACAP inhibit FasL expression in allogeneic effectors, and reduce Fas-mediated cytotoxicity against specific allotargets and syngeneic bystanders. VIP/PACAP also inhibit FasL expression in antigen-specific CD4(+) effectors, and reduce their cytotoxic activity against both the stimulatory APC, and syngeneic or allogeneic bystanders. Since bystander lysis is involved in the pathogenesis of several autoimmune and inflammatory diseases, the identification of regulatory factors that limit this process is highly significant.