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Myeloid-Derived Suppressor Cells Accumulate in Kidney Allograft Tolerance and Specifically Suppress Effector T Cell Expansion¹

Anne-Sophie Dugast^*, Thomas Haudebourg^*, Flora Coulon^*, Michèle Heslan^*, Fabienne Haspot^*, Nicolas Poirier^*, Romain Vuillefroy de Silly^*, Claire Usal^*, Helga Smit^*, Bernard Martinet^*, Pamela Thebault^*, Karine Renaudin and Bernard Vanhove^2,*

^* Institut National de la Santé et de la Recherche Médicale, U643, Centre Hospitalier Universitaire Nantes, Institut de Transplantation et de Recherche en Transplantation, Université de Nantes, Faculté de Médecine, Nantes; and Service d’Anatomie Pathologique du Centre Hospitalier Universitaire de Nantes, Nantes, France

The immune tolerance to rat kidney allografts induced by a perioperative treatment with anti-CD28 Abs is associated with a severe unresponsiveness of peripheral blood cells to donor Ags. In this model, we identified an accumulation in the blood of CD3^–class II^–CD11b⁺CD80/86⁺ plastic-adherent cells that additionally expressed CD172a as well as other myeloid markers. These cells were able to inhibit proliferation, but not activation, of effector T cells and to induce apoptosis in a contact-dependent manner. Their suppressive action was found to be under the control of inducible NO synthase, an enzyme also up-regulated in tolerated allografts. Based on these features, these cells can be defined as myeloid-derived suppressor cells (MDSC). Interestingly, CD4⁺CD25^highFoxP3⁺ regulatory T cells were insensitive in vitro to MDSC-mediated suppression. Although the adoptive transfer of MDSC failed to induce kidney allograft tolerance in recently transplanted recipients, the maintenance of tolerance after administration of anti-CD28 Abs was found to be dependent on the action of inducible NO synthase. These results suggest that increased numbers of MDSC can inhibit alloreactive T cell proliferation in vivo and that these cells may participate in the NO-dependent maintenance phase of tolerance.

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 in part by the Roche Organ Transplant Research Foundation Grant 466230972 (to B.V.) and by the Progreffe Fundation.

² Address correspondence and reprint requests to Dr. Bernard Vanhove, Institut de Transplantation et de Recherche en Transplantation, Institut National de la Santé et de la Recherche Médicale U643, Centre Hospitalier Universitaire Hôtel Dieu, 30 boulevard Jean Monnet, 44093 Nantes Cedex 1, France. E-mail address: Bernard.Vanhove{at}univ-nantes.fr

³ Abbreviations used in this paper: Treg, regulatory T cell; HO-1, heme oxygenase-1; iNOS, inducible NO synthase; L-NMMA, N^G-monomethyl-L-arginine; MDSC, myeloid-derived suppressor cells; 1-MT, 1-methyl-D,L-tryptophan; SIRP, signal regulatory protein ; SnPP, tin protoporphyrin.

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