MHC class II and CD40 play opposing roles in dendritic cell survival.
In contrast to very immature dendritic cells (DC), mature DC are largely resistant to death by CD95 (CD95/APO-1) ligation. Investigation of other potential death-inducing ligands showed that mature DC were instead highly susceptible to apoptosis induced by cross-linking of MHC class II. Thus, increasing DC maturity correlates with increased resistance to CD95 killing, but an increased susceptibility to class II-mediated killing. Anti-I-A/I-E monoclonal antibodies (mAb) induced rapid (<2 h) apoptotic cell death in mature epidermal, spleen and bone marrow-derived DC, as determined by annexin/propidium iodide staining, morphological changes, decreased diploidy and loss in mitochondrial membrane potential. Although full class II-mediated killing required DC cytoskeletal motion, divalent cations and phosphatase activity, neither caspase activation, respiration, RNA or protein synthesis, NO production, nor CD95:CD95L interactions were required. Strikingly, DC pretreated by CD40 mAb cross-linking, but not by lipopolysaccharide or TNF-alpha, were completely resistant to class II-mediated killing. CD40-mediated protection was reduced in the presence of the SB202190 inhibitor of the mitogen-activated protein kinase p38 pathway, but appeared to be independent of p42/44 extracellular signal-related kinase or NF-KB activation. Our findings show that in addition to its role as an activator of antigen-presenting cell function, CD40 provides an important counter-signal against class II-induced apoptosis. Thus, these data point to an important role of the T cell in regulating DC survival.
McLellan
A
A
Department of Dermatology, University of Würzburg, Germany.
Heldmann
M
M
Terbeck
G
G
Weih
F
F
Linden
C
C
Bröcker
E B
EB
Leverkus
M
M
Kämpgen
E
E
D000818:Animals; D017209:Apoptosis; D019013:CD40 Antigens / Q000502:physiology*; D023201:CD40 Ligand; D002470:Cell Survival; D003713:Dendritic Cells / Q000502:physiology*; D000949:Histocompatibility Antigens Class II / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D019014:fas Receptor / Q000032:analysis
D019013:CD40 Antigens; D000949:Histocompatibility Antigens Class II; D008562:Membrane Glycoproteins; D019014:fas Receptor; D023201:CD40 Ligand