CD40 ligation ablates the tolerogenic potential of lymphoid dendritic cells

The outcome of dendritic cell (DC) presentation of P815AB, a tolerogenic tu mor/self peptide, depends on a balance between the respective immunogenic a nd tolerogenic properties of myeloid (CD8 alpha (-)) and lymphoid (CD8 alph a (+)) DC. We have previously shown that CD8(-) DC can be primed by IL-12 t o overcome inhibition by the CD8(+) subset and initiate immunogenic present ation in vivo when the two types of peptide-pulsed DC are cotransferred int o recipient hosts. IFN-gamma enhances the inhibitory activity of CD8(+) DC on Ag presentation by the other subset, blocking the ability of IL-12-treat ed 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-gammaR expression and tryptophan -degrading ability. This effect was accompanied in vitro by an impaired cap acity of the CD40-modulated and IFN-gamma -treated DC to initiate T cell ap optosis, In vivo, not only did CD40 triggering on lymphoid DC abrogate thei r tolerogenic activity, but it also induced the potential for immunogenic p resentation 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 c ells in nonobese diabetic mice.