T cells recognizing self proteins exist without causing autoimmunity in healthy individuals. These autoreactive T cells are kept in check by peripheral tolerance. Using a model for peripheral CD8+ T cell tolerance resulting from antigen presentation by resting dendritic cells in vivo, we show here that CD8+ T cell tolerance operates through T cell–intrinsic mechanisms such as deletion or functional inactivation. Peripheral CD8+ T cell tolerance depended on signaling via the costimulatory molecule PD-1, as an absence of PD-1 converted tolerance induction into priming. Blocking of the costimulatory molecule CTLA-4 resulted in impaired tolerance and enhanced the effect of the absence of PD-1, suggesting that PD-1 and CTLA-4 act synergistically. Thus PD-1 and CTLA-4 are crucial molecules for peripheral CD8+ T cell tolerance induced by resting dendritic cells.
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We thank K. Tschannen for technical assistance; M. Delic, J. Fehr and W. Kehrli for animal husbandry; A. Macpherson for reviewing this manuscript and for discussions; and R. Zinkernagel and H. Hengartner for discussions and support. Supported by the Swiss National Science Foundation, the Max Cloëtta Foundation Zurich, the European Community (QLG1-CT-1999-2002) and the Swiss Bundesamt für Bildung und Wissenschaft.
The authors declare no competing financial interests.
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