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IFN-, as Secreted during an Alloresponse, Induces Differentiation of Monocytes into Tolerogenic Dendritic Cells, Resulting in FoxP3⁺ Regulatory T Cell Promotion¹

Immunogenomics Unit, Equipe d'Accueil 4130, Hôpital Edouard Herriot, Lyon, France and Université Claude Bernard Lyon I, Villeurbanne, France

IFN- has been shown to inhibit monocyte (Mo) differentiation into mature dendritic cells (DC). Because IFN- also plays a role in tolerance induction, we asked whether this could be related to generation of tolerogenic DC (Tol-DC). Toward this aim, we cultured Mo with GM-CSF plus IL-4 in the presence or absence of IFN- for 6 days and induced their maturation with TNF- for 2 additional days. We showed that IFN- deviated Mo differentiation from mature DC toward Tol-DC. Indeed, IFN--generated DC 1) expressed moderate levels of costimulatory molecules, but high levels of Langerin and CD123 molecules, 2) were maturation resistant, and 3) were unable to efficiently present alloantigen to T cells. More interestingly, naive CD4⁺ T cells primed with IFN--generated DC expressed FoxP3 mRNA at high levels and exerted regulatory functions upon secondary stimulation with alloantigen. To address whether endogenously secreted IFN- mediates a similar effect, we used the alloreaction as a model. We showed that cell-free supernatant harvested from an HLA-mismatched, but not HLA-identical, alloresponse induced differentiation of Mo into Tol-DC able to promote regulatory T cell generation. Moreover, when supplemented with GM-CSF plus IL-4, HLA-mismatched cell-free supernatant inhibited differentiation of Mo into mature DC. Finally, by adding Abs directed against inflammatory cytokines, we demonstrated that IFN- plays a preponderant role in this inhibition. In conclusion, our results clearly demonstrate that exogenous or endogenous IFN-, as well, induces differentiation of Mo toward Tol-DC, which results in FoxP3⁺ regulatory T cell promotion.

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 by grants to Assia Eljaafari from the Hospices Civils de Lyon, the Agence de Biomedicine, and the CENTAURE Foundation.

² Address correspondence and reprint requests to Dr. Assia Eljaafari, Hôpital Edouard Herriot, Pavillon P, 5 place d'Arsonval, 69003 Lyon, France. E-mail address: assia.eljaafari{at}chu-lyon.fr (copy to aeljaafari{at}aol.com)

³ Abbreviations used in this paper: Treg, regulatory T cell; CPB, cyclophilin B; DC, dendritic cell; GM/IL-4, GM-CSF plus IL-4; idCFS, identical cell-free supernatant; mmCFS, mismatched cell-free supernatant; Mo, monocyte; Tol-DC, tolerogenic dendritic cell.

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