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

Marco Gargaro, Giulia Scalisi, Giorgia Manni, Carlos G. Briseño, Prachi Bagadia, Vivek Durai, Derek J. Theisen, Sunkyung Kim, Marilena Castelli, Chenling A. Xu, Gerd Meyer zu Hörste, Giuseppe Servillo, Maria A. Della Fazia, Giulia Mencarelli, Doriana Ricciuti, Eleonora Padiglioni, Nicola Giacchè, Carolina Colliva, Roberto Pellicciari, Mario CalvittiTeresa Zelante, Dietmar Fuchs, Ciriana Orabona, Louis Boon, Alban Bessede, Marco Colonna, Paolo Puccetti, Theresa L. Murphy, Kenneth M. Murphy, Francesca Fallarino

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1032-1050.e14
JournalImmunity
Volume55
Issue number6
DOIs
StatePublished - Jun 14 2022

Keywords

  • AhR
  • IDO1
  • IL-6
  • RelB
  • dendritic cells
  • immunotolerance
  • kynurenine
  • metabolites
  • neuroinflammation
  • tryptophan metabolism

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