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Induction of Regulatory T Cells and Dominant Tolerance by Dendritic Cells Incapable of Full Activation¹

Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom

Transplants tolerated through a process known as infectious tolerance evoke continuous recruitment of regulatory T (Treg) cells that are necessary to maintain the unresponsive state. This state is maintained long-term and requires continuous Ag exposure. It is not known, however, whether infectious tolerance operates through sustained recruitment of pre-existing regulatory cells, induction of regulatory cells, or both. Using mice deficient in natural Treg cells, we show here that quiescent donor dendritic cells (DC) laden with histocompatibility Ag can induce Treg cells de novo that mediate transplantation tolerance. In contrast, fully activated DC fail to do so. These findings suggest that DC incapable of delivering full activation signals to naive T cells may favor their polarization toward a regulatory phenotype. Furthermore, they suggest a role for quiescent endogenous DC in the maintenance of the tolerant state.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants G7904009 and G0300230 from the Medical Research Council (U.K.) and by Reprogramming the Immune System for the Establishment of Tolerance, a European Community 6th Framework Programme (No. 512090). Microarray infrastructure was established with support from the Edward Penley Abraham Fund Cephalosporin Trust.

² Address correspondence and reprint requests to Prof. Herman Waldmann, Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, U.K. E-mail address: herman.waldmann{at}path.ox.ac.uk

³ H.W. and P.J.F. contributed equally to this work as senior authors.

⁴ Abbreviations used in this paper: Treg, regulatory T; APL, altered peptide ligand; DC, dendritic cell; bmDC, bone marrow-derived DC; 1,25(OH)₂D₃, 1,25 dihydroxyvitamin D₃; GITR, glucocorticoid-induced TNFR; 7-AAD, 7-aminoactinomycin D.

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