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Inducing and expanding regulatory T cell populations by foreign antigen

Abstract

Evidence suggests that regulatory T cells expressing the transcription factor Foxp3 develop extrathymically and intrathymically. Mechanisms of extrathymic induction require further scrutiny, especially as proliferation and/or phenotypic changes of preexisting suppressor cells must be distinguished from true de novo generation. Here we report the conversion of truly naive CD4+ T cells into suppressor cells expressing Foxp3 by targeting of peptide-agonist ligands to dendritic cells and by analysis of Foxp3 expression at the level of single cells. We show that conversion was achieved by minute antigen doses with suboptimal dendritic cell activation. The addition of transforming growth factor-β or the absence of interleukin 2 production, which reduces proliferation, enhanced the conversion rate. In addition, regulatory T cell populations induced in subimmunogenic conditions could subsequently be expanded by delivery of antigen in immunogenic conditions. The extrathymic generation and proliferation of regulatory T cells may contribute to self-tolerance as well as the poor immunogenicity of tumors and may be exploited clinically to prevent or reverse unwanted immunity.

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Figure 1: Conversion of naive CD4+CD25 T cells into CD4+CD25+ T cells.
Figure 2: Foxp3 expression and antigen-specific suppression by CD4+CD25+ T cells generated de novo.
Figure 3: Efficient induction of CD4+CD25+ regulatory T cells requires low doses of anti-DEC–HA and lack of costimulation.
Figure 4: Inverse relationship of cell division and CD25 expression.
Figure 5: Impaired TGF-βR signaling diminishes conversion of naive T cells into CD4+CD25+ regulatory T cells.
Figure 6: Costimulation of naive CD4+CD25 T cells in vitro by TCR and TGF-β receptor.
Figure 7: In vivo conversion of naive CD4+CD25 T cells costimulated in vitro with TCR and TGF-β.
Figure 8: Efficient conversion of Il2−/−CD4+CD25 naive T cells into regulatory T cells.

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Acknowledgements

We thank A. Krueger and P. Ruchala (von Boehmer lab) and all members of the Flow Cytometry Facility at the Dana-Farber Cancer Institute for technical help in cell sorting; A. Rolink (University of Basel, Basel, Switzerland) for providing the FGK 45 hybridoma; J. Polansky for antibody purification; and T. Hunig (University of Wurzburg, Wurzburg, Germany) for the gift of IL-2-deficient mice. Supported by the German Research Foundation (KR2316/1-1to K.K.) and the National Institutes of Health (R37 AI53102).

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Correspondence to Harald von Boehmer.

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Kretschmer, K., Apostolou, I., Hawiger, D. et al. Inducing and expanding regulatory T cell populations by foreign antigen. Nat Immunol 6, 1219–1227 (2005). https://doi.org/10.1038/ni1265

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