CD40 ligation counteracts Fas-induced apoptosis of human dendritic cells

Dendritic cells (DC) are cells of the hematopoietic system specialized in capturing antigens and initiating T cell-mediated immune responses, We show here that human DC generated in vitro by culturing CD34(+) cord blood progenitor cells in granulocyte macrophage colony stimulating factor plus tumor necrosis factor-alpha express the Pas antigen (APO-1, CD95) and undergo apoptosis upon triggering of Pas by mAb, However, only a proportion of the cells die in response to Fas ligation, an observation that may be related to the virtual absence of the bcl-2 protein in about half of the cells, Ligation of DC CD40 by culture on CD40L-transfected fibroblastic cells up-regulates the expression of bcl-2 and, concomitantly, renders DC virtually resistant to Pas-induced apoptosis, Parallel experiments with mature, interdigitating dendritic cells (IDC) isolated from tonsils revealed that IDC express Pas but do not enter into apoptosis following Pas ligation, a finding that may be explained by their high levels of bcl-2, Thus, upon encountering antigen-specific T cells, DC become resistant to Pas-induced apoptosis, as a consequence of CD40 ligation and possibly by mechanisms associated to the up-regulation of bcl-2 protein expression.