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Tolerogenic dendritic cells actively inhibit T cells through heme oxygenase-1 in rodents and in nonhuman primates

A. Moreau^*, M. Hill^,,, P. Thébault^,,, J. Y. Deschamps^||, E. Chiffoleau^,,, C. Chauveau^,,, P. Moullier^*, I. Anegon^,,, B. Alliot-Licht^,,,1 and M. C. Cuturi^,,,1,2

^* INSERM U649, CHU Hotel-Dieu, Nantes, France;

INSERM U643, Nantes, France;

CHU Nantes, Institut de Transplantation et de Recherche en Transplantation, Nantes, France;

Université de Nantes, Faculté de Médecine, Nantes, France; and

^|| Ecole Nationale Vétérinaire de Nantes, Service d’Urgence, Nantes, France

² Correspondence: INSERM U643 CHU Hotel-Dieu, 30 Bd. Jean Monnet, 44093 Nantes cedex 01 France. E-mail: maria-cristina.cuturi{at}univ-nantes.fr

Clinical translation of dendritic cell (DC)-based cell therapy requires preclinical studies in nonhuman primates (NHPs). The aim of this work was to establish the in vitro conditions for generation of NHP tolerogenic DCs (Tol-DCs), as well as to analyze the molecular mechanisms by which these cells could control an immune response. Two populations of NHP bone marrow-derived DCs (BMDCs) were obtained: adherent and nonadherent. Although both populations displayed a quite similar phenotype, they were very different functionally. We characterized the adherent BMDCs as Tol-DCs that were poor stimulators of T cells and actively inhibited T-cell proliferation, whereas the nonadherent population displayed immunogenic properties in vitro. Interestingly, the anti-inflammatory and immunosuppressive enzyme heme oxygenase-1 (HO-1) was up-regulated in Tol-DCs, compared to the immunogenic BMDCs. We demonstrated that HO-1 mediates the immunosuppressive properties of Tol-DCs in vitro (in NHPs and rats) and that HO-1 is involved in the in vivo tolerogenic effect of Tol-DCs in a rat model of allotransplantation. In conclusion, here we characterized the in vitro generation of NHP Tol-DCs. Furthermore, we showed for the first time that HO-1 plays a role in the active inhibition of T-cell responses by rat and NHP Tol-DCs.—Moreau, A., Hill, M., Thébault, P., Deschamps, J. Y., Chiffoleau, E., Chauveau, C., Moullier, P., Anegon, I., Alliot-Licht, B., Cuturi M. C. Tolerogenic dendritic cells actively inhibit T cells through heme oxygenase-1 in rodents and in nonhuman primates.

Key Words: immune tolerance • cell therapy • macaque

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