Dendritic cell secretion of IL-15 is induced by recombinant huCD40LT and augments the stimulation of antigen-specific cytolytic T cells

Dendritic cells (DC) are professional antigen-presenting cells which stimul ate strong proliferative and cytolytic T cell responses, Stimulation of CD4 0 on dendritic cells by its ligands and anti-CD40 antibodies induces matura tion and enhances DC stimulatory ability. In order to understand the mechan ism by which ligand:CD40 interactions augment DC function, we assessed the role of T cell stimulatory cytokines IL-12 and IL-15 in the function of DC stimulated with soluble trimeric CD40L, a recombinant fusion protein incorp orating three covalently linked extracellular CD40L domains (huCD40LT). Per ipheral blood derived DC treated with huCD40LT and/or IFN-gamma were used t o stimulate T cell responses in vitro to specific antigens. DC treated with huCD40LT or IFN-gamma/ huCD40LT stimulated enhanced T cell proliferation t o CASTA, a soluble protein from C. albicans, induced T cells with augmented antigen-specific lysis, and increased the yield of antigen-specific IFN-ga mma-producing T cells. IL-15 production by DC was enhanced in cultures trea ted with huCD40LT and correlated with expansion of antigen-specific cytolyt ic T cells. Addition of a neutralizing anti-IL-15 monoclonal antibody inhib ited the expansion of viral and tumor antigen-specific T cells stimulated b y IFN-gamma and huCD40LT-treated DC. In contrast, this enhanced stimulatory ability of DC did not appear to depend on synthesis of IL-12 since huCD40L T treatment stimulated the generation of antigen-specific cytokine producin g and cytolytic T cells without increased IL-12 production. Addition of ant i-IL-12 monoclonal antibody did not inhibit expansion of these cells. These data suggest that production of IL-15 but not LT-12 is an important factor in the enhanced immunostimulatory ability of huCD40LT-treated DC. (C) 1999 Academic Press.