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Blood, 1 February 2006, Vol. 107, No. 3, pp. 1031-1038. Prepublished online as a Blood First Edition Paper on October 11, 2005; DOI 10.1182/blood-2005-04-1737. This Article Full Text (PDF) All Versions of this Article: 2005-04-1737v1 107/3/1031    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kadowaki, N. Articles by Uchiyama, T. Search for Related Content PubMed PubMed Citation Articles by Kadowaki, N. Articles by Uchiyama, T. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 28, 2005 Accepted September 25, 2005 Virus-stimulated plasmacytoid dendritic cells induce CD4+ cytotoxic regulatory T cells Norimitsu Kadowaki*, Kazuko Kawamura, Toshio Kitawaki, and Takashi Uchiyama Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan * Corresponding author; email: kadowaki{at}kuhp.kyoto-u.ac.jp. Immune responses to pathogens need to be maintained within appropriate levels to minimize tissue damage, whereas such controlled immunity may allow persistent infection of certain types of pathogens. Interleukin (IL)-10 plays an important role in such immune regulation. We previously showed that herpes simplex virus (HSV)-stimulated human plasmacytoid dendritic cells (pDCs) induce naive CD4+ T cells to differentiate into interferon (IFN)-/IL-10-producing T cells. Here we show that HSV-stimulated pDCs induce allogeneic naive CD4+ T cells to differentiate into cytotoxic regulatory T cells that poorly proliferate upon re-stimulation and inhibit proliferation of co-existing naive CD4+ T cells. IL-3-stimulated pDCs or myeloid DCs did not induce such regulatory T cells. Both IFN- and IL-10 were responsible for the induction of anergic and regulatory properties. High percentages of CD4+ T cells co-cultured with HSV-stimulated pDCs, and to a lesser extent those co-cultured with IL-3-stimulated pDCs, expressed granzyme B and perforin in an IL-10-dependent manner. CD4+ T cells co-cultured with HSV-stimulated pDCs accordingly exhibited cytotoxic activity. The finding that virus-stimulated pDCs are capable of inducing CD4+ cytotoxic regulatory T cells suggests that this DC subset may play an important role in suppressing excessive inflammatory responses and also in inducing persistent viral infection. 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