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Blood, 1 October 2006, Vol. 108, No. 7, pp. 2265-2274.
Prepublished online as a Blood First Edition Paper on June 1, 2006; DOI 10.1182/blood-2006-02-004762.


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IMMUNOBIOLOGY

Thymosin {alpha}1 activates dendritic cell tryptophan catabolism and establishes a regulatory environment for balance of inflammation and tolerance

Luigina Romani, Francesco Bistoni, Katia Perruccio, Claudia Montagnoli, Roberta Gaziano, Silvia Bozza, Pierluigi Bonifazi, Giovanni Bistoni, Guido Rasi, Andrea Velardi, Francesca Fallarino, Enrico Garaci, and Paolo Puccetti

From the Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy; Division of Hematology and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy; Institute of Neurobiology and Molecular Medicine, National Council of Research (CNR), Rome, Italy; and National Institute of Health, Rome, Italy.

Thymosin {alpha}1 (T{alpha}1), 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 T{alpha}1 for possible induction of DC-dependent regulatory effects. T{alpha}1 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 T{alpha}1 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, T{alpha}1-primed DCs fulfilled multiple requirements, including the induction of T-helper type 1 immunity within a regulatory environment. Thus, instructive immunotherapy with T{alpha}1 targeting IDO-competent DCs could allow for a balanced control of inflammation and tolerance.


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