MHC class II and CD40 play opposing roles in dendritic cell survival

In contrast to very immature dendritic cells (DC), mature DC are largely re sistant to death by CD95 (CD95/APO-1) ligation. Investigation of other pote ntial death-inducing ligands showed that mature DC were instead highly susc eptible to apoptosis induced by cross-linking of MHC class II. Thus, increa sing DC maturity correlates with increased resistance to CD95 killing, but an increased susceptibility to class II-mediated killing. Anti-I-A/I-E mono clonal antibodies (mAb) induced rapid (<2 h) apoptotic cell death in mature epidermal, spleen and bone marrow-derived DC, as determined by annexin/pro pidium iodide staining, morphological changes, decreased diploidy and loss in mitochondrial membrane potential. Although full class II-mediated killin g required DC cytoskeletal motion, divalent cations and phosphatase activit y, neither caspase activation, respiration, RNA or protein synthesis, NO pr oduction, nor CD95:CD95L interactions were required. Strikingly, DC pretrea ted by CD40 mAb crosslinking, but not by lipopolysaccharide or TNF-alpha, w ere completely resistant to class II-mediated killing. CD40-mediated protec tion was reduced in the presence of the SB202190 inhibitor of the mitogen-a ctivated protein kinase p38 pathway, but appeared to be independent of p42/ 44 extracellular signal-related kinase or NF-KB activation. Our findings sh ow that in addition to its role as an activator of antigen-presenting cell function, CD40 provides an important counter-signal against class II-induce d apoptosis. Thus, these data point to an important role of the T cell in r egulating DC survival.