CD40 ligation ablates the tolerogenic potential of lymphoid dendritic cells.
The outcome of dendritic cell (DC) presentation of P815AB, a tolerogenic tumor/self peptide, depends on a balance between the respective immunogenic and tolerogenic properties of myeloid (CD8 alpha(-)) and lymphoid (CD8 alpha(+)) DC. We have previously shown that CD8(-) DC can be primed by IL-12 to overcome inhibition by the CD8(+) subset and initiate immunogenic presentation in vivo when the two types of peptide-pulsed DC are cotransferred into recipient hosts. IFN-gamma enhances the inhibitory activity of CD8(+) DC on Ag presentation by the other subset, blocking the ability of IL-12-treated CD8(-) DC to overcome suppression. We report here that CD40 ligation on lymphoid DC ablated their inhibitory function on Ag presentation as well as IFN-gamma potentiation of the effect. CD40 modulation of IFN-gamma action on lymphoid DC involved a reduction in IFN-gamma R expression and tryptophan-degrading ability. This effect was accompanied in vitro by an impaired capacity of the CD40-modulated and IFN-gamma-treated DC to initiate T cell apoptosis. In vivo, not only did CD40 triggering on lymphoid DC abrogate their tolerogenic activity, but it also induced the potential for immunogenic presentation of P815AB. Importantly, a pattern similar to P815AB as well as CD40 modulation of lymphoid DC function were observed on testing reactivity to NRP, a synthetic peptide mimotope recognized by diabetogenic CD8(+) T cells in nonobese diabetic mice.
Grohmann
U
U
Department of Experimental Medicine, University of Perugia, Perugia, Italy.
Fallarino
F
F
Silla
S
S
Bianchi
R
R
Belladonna
M L
ML
Vacca
Carmine
C
Micheletti
A
A
Fioretti
M C
MC
Puccetti
P
P
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism; D017209:Apoptosis / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology* / Q000378:metabolism* / Q000502:physiology; D016827:CD8 Antigens / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology; D015536:Down-Regulation / Q000276:immunology; D004790:Enzyme Induction / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D008024:Ligands; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D016688:Mice, Inbred NOD; D018716:Molecular Mimicry / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D017471:Receptors, Interferon / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D013154:Spleen / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D014366:Tryptophan Oxygenase / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D000096743:Interferon gamma Receptor
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D019013:CD40 Antigens; D016827:CD8 Antigens; D007371:Interferon-gamma; D008024:Ligands; D010446:Peptide Fragments; D017471:Receptors, Interferon; D014366:Tryptophan Oxygenase; D000096743:Interferon gamma Receptor; C076546:tumor rejection antigen P815A, mouse