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J Immunol. 2014 Dec 15;193(12):5863-72. doi: 10.4049/jimmunol.1400758. Epub 2014 Oct 31.

Glucocorticoid-induced leucine zipper enhanced expression in dendritic cells is sufficient to drive regulatory T cells expansion in vivo.

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INSERM U996, Clamart, 92 140, France; Faculté de Médecine, Université Paris-Sud, Le Kremlin Bicêtre, 94 275, France;
INSERM U996, Clamart, 92 140, France; Faculté de Pharmacie, Université Paris-Sud, Chatenay Malabry, 92 296, France;
INSERM U996, Clamart, 92 140, France;
INSERM U996, Clamart, 92 140, France; Faculté de Médecine, Université Paris-Sud, Le Kremlin Bicêtre, 94 275, France;
INSERM U955, Eq16, Créteil, 94 000, France; Vaccine Research Institute, Créteil, 94 000, France; and Université Paris Est, Faculté de Médecine, Créteil, 94 000, France


Tolerance induction by dendritic cells (DCs) is, in part, mediated by the activation of regulatory T cells (Tregs). We have previously shown in vitro that human DCs treated with glucocorticoids (GCs), IL-10, or TGF-β upregulate the GC-Induced Leucine Zipper protein (GILZ). GILZ overexpression promotes DC differentiation into regulatory cells that generate IL-10-producing Ag-specific Tregs. To investigate whether these observations extend in vivo, we have generated CD11c-GILZ(hi) transgenic mice. DCs from these mice constitutively overexpress GILZ to levels observed in GC-treated wild-type DCs. In this article, we establish that GILZ(hi) DCs display an accumulation of Foxp3(+) Tregs in the spleens of young CD11c-GILZ(hi) mice. In addition, we show that GILZ(hi) DCs strongly increase the Treg pool in central and peripheral lymphoid organs of aged animals. Upon adoptive transfer to wild-type recipient mice, OVA-loaded GILZ(hi) bone marrow-derived DCs induce a reduced activation and proliferation of OVA-specific T cells as compared with control bone marrow-derived DCs, associated with an expansion of thymus-derived CD25(+)Foxp3(+) CD4 T cells. Transferred OVA-loaded GILZ(hi) DCs produce significantly higher levels of IL-10 and express reduced levels of MHC class II molecules as compared with OVA-loaded control DCs, emphasizing the regulatory phenotype of GILZ(hi) DCs in vivo. Thus, our work demonstrates in vivo that the GILZ overexpression alone is sufficient to promote a tolerogenic mode of function in DCs.

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