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Indoleamine 2,3-dioxygenase 1 activation in mature cDC1 promotes tolerogenic education of inflammatory cDC2 via metabolic communication

Gargaro, M;Scalisi, G;Manni, G;Briseño, CG;Bagadia, P;Durai, V;Theisen, DJ;Kim, S;Castelli, M;Xu, CA;Zu Hörste, GM;Servillo, G;Della Fazia, MA;Mencarelli, G;Ricciuti, D;Padiglioni, E;Giacchè, N;Colliva, C;Pellicciari, R;Calvitti, M;Zelante, T;Fuchs, D;Orabona, C;Boon, L;Bessede, A;Colonna, M;Puccetti, P;Murphy, TL;Murphy, KM;Fallarino, F;

Conventional dendritic cells (cDCs), cDC1 and cDC2, act both to initiate immunity and maintain self-tolerance. The tryptophan metabolic enzyme indoleamine 2,3-dioxygenase 1 (IDO1) is used by cDCs in maintaining tolerance, but its role in different subsets remains unclear. At homeostasis, only mature CCR7+ cDC1 expressed IDO1 that was dependent on IRF8. Lipopolysaccharide treatment induced maturation and IDO1-dependent tolerogenic activity in isolated immature cDC1, but not isolated cDC2. However, both human and mouse cDC2 could induce IDO1 and acquire tolerogenic function when co-cultured with mature cDC1 through the action of cDC1-derived l-kynurenine. Accordingly, cDC1-specific inactivation of IDO1 in vivo exacerbated disease in experimental autoimmune encephalomyelitis. This study identifies a previously unrecognized metabolic communication in which IDO1-expressing cDC1 cells extend their immunoregulatory capacity to the cDC2 subset through their production of tryptophan metabolite l-kynurenine. This metabolic axis represents a potential therapeutic target in treating autoimmune demyelinating diseases.