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Suppression of Mature Dendritic Cell Function by Regulatory T Cells In Vivo Is Abrogated by CD40 Licensing¹

Department of Dermatology, University Hospital Erlangen, Erlangen; and Institute for Virology and Immunobiology, University of Wuerzburg, Wuerzburg, Germany

The priming of CD4⁺ effector T cells (T_eff) in vivo is induced by mature dendritic cells (DC) and controlled by CD4⁺CD25⁺Foxp3⁺ regulatory T cells (T_reg). It remains unclear,however, how T_eff priming vs T_reg suppression are regulated during Ag presentation by DC in secondary lymphoid organs at the simultaneous presence of T_eff and T_reg. In this study, we used an peptide-specific DO11.10 TCR-transgenic adoptive transfer model to follow the T_eff priming kinetics and the mechanisms of suppression by T_reg. T_reg activation was slower as compared with T_eff and could not influence the early T_eff expansion but limited the T_eff response leading to lower T_eff numbers in the memory phase. DC-T_reg cell contacts remained unaltered during suppression by T_reg and led to a down-regulation of the costimulatory molecules CD80, CD86, PD-L1, and PD-L2 but not MHC II, CD40, ICOS-L, or CD70 from the mature DC surface. This effect was observed only after DC maturation with TNF or LPS but not after additional CD40 licensing. Together, our data indicate that T_reg suppression against nonself Ags in vivo occurs delayed due to the slower T_reg response, is mediated to a large extent through DC modulation, but is controlled by the type of DC maturation.

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 the Deutsche Forschungsgemeinschaft through the Research Training Group GK 592, the Collaborative Research Center SFB 643 in Erlangen, and the Institute of Virology and Immunobiology in Wuerzburg.

² Address correspondence and reprint requests to Dr. Manfred B. Lutz, University of Wuerzburg, Versbacherstrasse 7, Wuerzburg 97987, Germany. E-mail address: m.lutz{at}vim.uni-wuerzburg.de

³ Abbreviations used in this paper: T_reg, CD25⁺ regulatory T cell; BM, bone marrow; DC, dendritic cell; T_eff, CD25^– effector T cells; CMAC, Cell Tracker Blue; CMTMR, Cell Tracker Orange.