CD40 ligation counteracts Fas-induced apoptosis of human dendritic cells

Abstract

Dendritic cells (DC) are cells of the hematopoletic 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 Fas antigen (APO-1, CD95) and undergo apoptosis upon triggering of Fas 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 Fas-induced apoptosis. Parallel experiments with mature, interdigitating dendritic cells (IDC) isolated from tonsils revealed that IDC express Fas but do not enter into apoptosis following Fas 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 Fas-induced apoptosis, as a consequence of CD40 ligation and possibly by mechanisms associated to the up-regulation of bcl-2 protein expression.

Langerhans Cells That Have Matured In Vivo in the Absence of T Cells Are Fully Capable of Inducing a Helper CD4 as Well as a Cytotoxic CD8 Response

“…T cells present in the draining lymph nodes may still be important in sustaining or abrogating an immune response by influencing the function of DCs through the interaction between CD40 and CD40L at the final stages in the life span of DCs. Signaling through CD40 ligation can rescue DC from Fas-induced apoptosis, which can determine this balance between sustaining or declining an immune response (47). Our results also indicate that cytokines produced by keratinocytes after Ag encounter may be sufficient to induce migration and maturation of LCs to the draining lymph nodes.…”

Dendritic Cells Genetically Engineered to Express Fas Ligand Induce Donor-Specific Hyporesponsiveness and Prolong Allograft Survival

“…In addition, several ligand/receptor interactions have been shown to affect the outcome of FasL/Fas interaction. For example, DC survival signals expressed on T cells, such as TRANCE and CD40L, can prevent Fas-induced apoptosis (55)(56)(57).…”

Cognate interactions between memory T cells and tumor antigen‐presenting dendritic cells from bone marrow of breast cancer patients: Bidirectional cell stimulation, survival and antitumor activity in vivo

“…37 Another molecule involved could be CD40, which we saw to be significantly upregulated on DC from cognate cocultures. CD40 ligation was described to counteract Fas-induced apoptosis of human DCs, 38 to ablate the tolerigenic potential of lymphoid dendritic cells 39 and to be essential for the generation of CTLs from naive polyclonal CD8 T cells. 40 Furthermore, DC longevity and T-cell persistence was reported to be controlled by CD40-CD154 interactions.…”