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Antigen-Driven Interactions with Dendritic Cells and Expansion of Foxp3⁺ Regulatory T Cells Occur in the Absence of Inflammatory Signals¹

Pascal Chappert^*, Marylène Leboeuf^*, Philippe Rameau^*, Daniel Stockholm^*, Roland Liblau, Olivier Danos^*,, Jean M. Davoust^2,3,*, and David-Alexandre Gross^2,3,*

^* Genethon, Centre National de la Recherche Scientifique, Unité Mixte de Recherche, 8115, Évry, France; Institut National de la Santé et de la Recherche Médicale U563, Université Paul Sabatier, Hôpital Purpan, Toulouse, France; Université Paris Descartes, Institut National de la Santé et de la Recherche Médicale U781 and Institut National de la Santé et de la Recherche Médicale U580, Hôpital Necker-Enfants Malades, Paris, France

Foxp3⁺ regulatory T cells (Tregs) play a pivotal role in the maintenance of peripheral T cell tolerance and are thought to interact with dendritic cells (DC) in secondary lymphoid organs. We analyzed here the in vivo requirements for selective expansion of Ag-specific Treg vs CD4⁺CD25^– effector T cells and engagement of Ag-specific Treg-DC interactions in secondary lymphoid organs. Using i.v. Ag delivery in the absence of inflammation, we found that CD4⁺CD25⁺Foxp3⁺ Tregs undergo vigorous expansion and accumulate whereas naive CD4⁺CD25^–Foxp3^– T cells undergo abortive activation. Quantifying directly the interactions between Tregs and CD11c⁺ DC, we found that Tregs establish cognate contacts with endogenous CD11c⁺ DC in spleen and lymph nodes at an early time point preceding their expansion. Importantly, we observed that as few as 10³ Tregs selectively expanded by i.v. Ag injection are able to suppress B and T cell immune responses in mouse recipients challenged with the Ag. Our results demonstrate that Tregs are selectively mobilized by Ag recognition in the absence of inflammatory signals, and can induce thereafter potent tolerance to defined Ag targets.

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¹ This work was supported by the Association Française contre les Myopathies and by an Action Thématique Incitative du Génopole d’Evry grant from the Genopole Public Interest Group. P.R.C. is supported by the French Ministry of Research.

² J.M.D. and D.-A.G. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. David-Alexandre Gross and Dr. Jean M. Davoust, Genethon Centre National de la Recherche Scientifique FRE3018, 1 Bis Rue de L’internationale, Evry 91002, France. E-mail addresses: gross{at}genethon.fr and jean.davoust{at}necker.fr

⁴ Abbreviations used in this paper: Tregs, regulatory T cells; AAV, adeno-associated virus; HA, hemagglutinin.