title: Thymosin alpha1 activates dendritic cell tryptophan catabolism and establishes a regulatory environment for balance of inflammation and tolerance.
abstract: Thymosin alpha1 (Talpha1), a naturally occurring thymic peptide, primes dendritic cells (DCs) for antifungal T-helper type 1 resistance through Toll-like receptor 9 (TLR9) signaling. As TLR9 signaling also activates the immuno-suppressive pathway of tryptophan catabolism via indoleamine 2,3-dioxygenase (IDO), we examined Talpha1 for possible induction of DC-dependent regulatory effects. Talpha1 affected T-helper cell priming and tolerance induction by human and murine DCs and induced IDO expression and function in the latter cells. IDO activation by Talpha1 required TLR9 and type I interferon receptor signaling and resulted in interleukin-10 production and generation of regulatory T cells. In transfer experiments, functionally distinct subsets of differentiated DCs were required for priming and tolerance to a fungal pathogen or alloantigens. In contrast, Talpha1-primed DCs fulfilled multiple requirements, including the induction of T-helper type 1 immunity within a regulatory environment. Thus, instructive immunotherapy with Talpha1 targeting IDO-competent DCs could allow for a balanced control of inflammation and tolerance.
authors.affiliation: Dept of Experimental Medicine, Section of Microbiology, University of Perugia, Via del Giochetto, Perugia 06126, Italy. lromani@unipg.it
authors.forename: Luigina
authors.initials: L
authors.lastname: Romani
authors.forename: Francesco
authors.initials: F
authors.lastname: Bistoni
authors.forename: Katia
authors.initials: K
authors.lastname: Perruccio
authors.forename: Claudia
authors.initials: C
authors.lastname: Montagnoli
authors.forename: Roberta
authors.initials: R
authors.lastname: Gaziano
authors.forename: Silvia
authors.initials: S
authors.lastname: Bozza
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Bonifazi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Bistoni
authors.forename: Guido
authors.initials: G
authors.lastname: Rasi
authors.forename: Andrea
authors.initials: A
authors.lastname: Velardi
authors.forename: Francesca
authors.initials: F
authors.lastname: Fallarino
authors.forename: Enrico
authors.initials: E
authors.lastname: Garaci
authors.forename: Paolo
authors.initials: P
authors.lastname: Puccetti
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D001232:Aspergillus fumigatus / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D000077596:Thymalfasin; D013947:Thymosin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000502:physiology; D051217:Toll-Like Receptor 9 / Q000378:metabolism*; D014364:Tryptophan / Q000737:chemistry*
chemical_list: D000276:Adjuvants, Immunologic; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D051217:Toll-Like Receptor 9; D016753:Interleukin-10; D013947:Thymosin; D014364:Tryptophan; D000077596:Thymalfasin