Differential effect of agonistic anti-CD40 on human mature and immature dendritic cells: the Janus face of anti-CD40.
Agonistic monoclonal antibodies to CD40 (CD40 mAbs) have a puzzling dual therapeutic effect in experimental animal models. CD40 mAbs induce tumor regression by potentiating antitumoral T-cell responses, yet they also have immunosuppressive activity in chronic autoimmune inflammatory processes. CD40 mAbs are thought to act on antigen presentation by dendritic cells (DCs) to T cells. DCs can be distinguished as either immature or mature by their phenotype and their ability to generate an effective T-cell response. Here we found that, on human cells, although anti-CD40 led immature DCs to mature and became immunogenic, it also reduced the capacity of lipopolysaccharide (LPS) and tumor necrosis factor alpha (TNF-alpha)-matured DCs to generate a specific CD4 T-cell response. This inhibitory effect was related to rapid and selective apoptosis of mature DCs. Anti-CD40-mediated apoptosis was due to an indirect mechanism involving cooperation with the death domain-associated receptor Fas, leading to activation of Fas-associated death domain protein (FADD) and caspase-8. On human cells, CD40 activation by such agonists could, therefore, trigger immune responses to antigens presented by immature DCs, which are otherwise nonimmunogenic, by inducing maturation. On the other hand, anti-CD40 mAbs, by rapidly inducing apoptosis, may reduce the capacity of inflammatory signal-matured immunogenic DCs to generate an effective T-cell response. These results call for caution in CD40 mAb-based immunotherapy strategies.
INSERM E-109, 63, Faculty of Medicine, Rue Gabriel Péri, 94276 Le Kremlin-Bicêtre, France.
Marie-Ghislaine
MG
de Goër de Herve
Deniz
D
Durali
Tú-Anh
TA
Tran
Gwénola
G
Maigné
Federico
F
Simonetta
Philippe
P
Leclerc
Jean-François
JF
Delfraissy
Yassine
Y
Taoufik
D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D019013:CD40 Antigens / Q000276:immunology*; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology* / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D004789:Enzyme Activation; D053222:Fas Ligand Protein; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology
D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D020169:Caspases