Thymosin alpha1 activates dendritic cell tryptophan catabolism and establishes a regulatory environment for balance of inflammation and tolerance.
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.
Romani
Luigina
L
Dept of Experimental Medicine, Section of Microbiology, University of Perugia, Via del Giochetto, Perugia 06126, Italy. lromani@unipg.it
Bistoni
Francesco
F
Perruccio
Katia
K
Montagnoli
Claudia
C
Gaziano
Roberta
R
Bozza
Silvia
S
Bonifazi
Pierluigi
P
Bistoni
Giovanni
G
Rasi
Guido
G
Velardi
Andrea
A
Fallarino
Francesca
F
Garaci
Enrico
E
Puccetti
Paolo
P
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*
D000276:Adjuvants, Immunologic; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D051217:Toll-Like Receptor 9; D016753:Interleukin-10; D013947:Thymosin; D014364:Tryptophan; D000077596:Thymalfasin