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Differential Control of T Regulatory Cell Proliferation and Suppressive Activity by Mature Plasmacytoid versus Conventional Spleen Dendritic Cells¹

Asmahan Ouabed^2,*,,, Francois-Xavier Hubert^2,3,*,,, Dominique Chabannes^*,,, Laetitia Gautreau^*,,, Michèle Heslan^*,, and Régis Josien^4,*,,,

^* Institut National de la Santé et de la Recherche Médicale Unite 643, Centre Hospitalier Universitaire de Nantes, Institut de Transplantation et de Recherche en Transplantation-Urologie-Néphrologie, Université de Nantes, Faculté de Médecine, and Centre Hospitalier Universitaire de Nantes, Laboratoire d’Immunologie, Nantes, France

Anergy and suppression are cardinal features of CD4⁺CD25⁺Foxp3⁺ T cells (T regulatory cells (Treg)) which have been shown to be tightly controlled by the maturation state of dendritic cells (DC). However, whether lymphoid organ DC subsets exhibit different capacities to control Treg is unclear. In this study, we have analyzed, in the rat, the role of splenic CD4⁺ and CD4^– conventional DC and plasmacytoid DC (pDC) in allogeneic Treg proliferation and suppression in vitro. As expected, in the absence of exogenous IL-2, Treg did not expand in response to immature DC. Upon TLR-induced maturation, all DC became potent stimulators of CD4⁺CD25^– T cells, whereas only TLR7- or TLR9-matured pDC induced strong proliferation of CD4⁺CD25⁺Foxp3⁺ T cells in the absence of exogenous IL-2. This capacity of pDC to reverse Treg anergy required cell contact and was partially CD86 dependent and IL-2 independent. In suppression assays, Treg strongly suppressed proliferation and IL-2 and IFN- production by CD4⁺CD25^– T cells induced by mature CD4⁺ and CD4^– DC. In contrast, upon stimulation by mature pDC, proliferating Treg suppressed IL-2 production by CD25^– cells but not their proliferation or IFN- production. Taken together, these results suggest that anergy and the suppressive function of Treg are differentially controlled by DC subsets.

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¹ This work was supported by a Roche Organ Transplantation Research Foundation Grant 415394615 (to R.J.). A.O. was supported by a grant from the Algerian Ministère de l’enseignement supérieur et de la recherche scientifique. F.-X.H. was supported by a grant from Institut National de la Santé et de la Recherche Médicale-Région Pays de la Loire. L.G. was supported by the Fondation de Coopération Scientifique CENTAURE.

² A.O. and F.-X.H. contributed equally to this work.

³ Current address: Division of Immunology, Walter and Elisa Hall Institute of Medical Research, Melbourne, Australia.

⁴ Address correspondence and reprint requests to Dr. Régis Josien, Institut National de la Santé et de la Recherche Médicale Unite 643, Centre Hospitalier Universitaire Hotel Dieu, 30 boulevard Jean Monnet, 44093 Nantes, Cedex 1, France. E-mail address: Regis.Josien{at}univ-nantes.fr

⁵ Abbreviations used in this paper: Treg, T regulatory cell; Foxp3, forkhead box p3; DC, dendritic cell; pDC, plasmacytoid DC; cDC, conventional DC; L, ligand; DDAO-SE, 7-hydroxy-9H(I,3-dichloro-9,9-dimethylacridin-2-one succinimidyl ester; MHCII, MHC class II; BMDC, bone marrow-derived DC; Cy7, cyanin 7.