Tolerogenic dendritic cells actively inhibit T cells through heme oxygenase-1 in rodents and in nonhuman primates.
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.
INSERM U643, CHU Hotel-Dieu, Nantes, France.
A
A
Moreau
M
M
Hill
P
P
Thébault
J Y
JY
Deschamps
E
E
Chiffoleau
C
C
Chauveau
P
P
Moullier
I
I
Anegon
B
B
Alliot-Licht
M C
MC
Cuturi
D000818:Animals; D001854:Bone Marrow Cells; D002448:Cell Adhesion; D017690:Cell Transplantation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology* / Q000637:transplantation; D051547:Heme Oxygenase-1 / Q000235:genetics*; D007108:Immune Tolerance / Q000276:immunology*; D011323:Primates; D051381:Rats; D013601:T-Lymphocytes / Q000276:immunology*; D014184:Transplantation, Homologous; D015854:Up-Regulation / Q000235:genetics
D051547:Heme Oxygenase-1