Forced IDO 1 expression in dendritic cells restores immunoregulatory signalling in autoimmune diabetes

Indoleamine 2,3‐dioxygenase ( IDO 1), a tryptophan catabolizing enzyme, is recognized as an authentic regulator of immunity in several physiopathologic conditions. We have recently demonstrated that IDO 1 does not merely degrade tryptophan and produce immunoregulatory kynurenines, but it also acts as a signal‐transducing molecule, independently of its enzymic function. IDO 1 signalling activity is triggered in plasmacytoid dendritic cells ( pDC s) by transforming growth factor‐β ( TGF ‐β), an event that requires the non‐canonical NF ‐κB pathway and induces long‐lasting IDO 1 expression and autocrine TGF ‐β production in a positive feedback loop, thus sustaining a stably regulatory phenotype in p DC s. IDO 1 expression and catalytic function are defective in p DC s from non‐obese diabetic ( NOD ) mice, a prototypic model of autoimmune diabetes. In the present study, we found that TGF ‐β failed to activate IDO 1 signalling function as well as up‐regulate IDO 1 expression in NOD p DC s. Moreover, TGF ‐β‐treated p DC s failed to exert immunosuppressive properties in vivo . Nevertheless, transfection of NOD p DC s with Ido1 prior to TGF ‐β treatment resulted in activation of the Ido1 promoter and induction of non‐canonical NF ‐κB and TGF ‐β, as well as decreased production of the pro‐inflammatory cytokines, interleukin 6 ( IL ‐6) and tumour necrosis factor‐α ( TNF ‐α). Overexpression of IDO 1 in TGF ‐β‐treated NOD p DC s also resulted in p DC ability to suppress the in vivo presentation of a pancreatic β‐cell auto‐antigen. Thus, our data suggest that a correction of IDO 1 expression may restore its dual function and thus represent a proper therapeutic manoeuvre in this autoimmune setting.