IL-6 inhibits the tolerogenic function of CD8 alpha(+) dendritic cells expressing indoleamine 2,3-dioxygenase

The outcome of dendritic cell (DC) presentation of tumor and/or self peptid es, including P815AB (a tumor peptide of murine mastocytoma cells) and NRP- A7 (a synthetic peptide mimotope recognized by diabetogenic T cells), may d epend on a balance between the activities of immunogenic (CD8 alpha (-)) an d tolerogenic (CD8 alpha (+)) DC. By virtue of their respective actions on CD8(-) and CD8(+) DC, IL-12 and IFN-gamma have functionally opposing effect s on peptide presentation by the CD8(-) DC subset, and IFN-gamma -activated CD8(+) DC mediate tolerogenic effects that prevail over the adjuvant activ ity of IL-12 on CD8(-) DC. We have Previously shown that CD40 ligation abro gates the tolerogenic potential of CD8(+) DC, an effect associated with an impaired capacity of the CD40-modulated and IFN-gamma -treated DC to degrad e tryptophan and initiate T cell apoptosis in vitro. We report here that IL -6 may both replace (upon administration of the recombinant cytokine) and m ediate (as assessed by the use of neutralizing Abs) the effect of CD40 liga tion in ablating the tolerogenic activity of CD8(+) DC. The activity of IL- 6 includes down-regulation of IFN-gammaR expression in the CD8(+) DC subset and correlates to a reduced ability of these cells to metabolize tryptopha n and Initiate T cell apoptosis in vitro.