Glucocorticoid-Induced Leucine Zipper Enhanced Expression in Dendritic Cells Is Sufficient To Drive Regulatory T Cells Expansion In Vivo

Abstract

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-GILZhi transgenic mice. DCs from these mice constitutively overexpress GILZ to levels observed in GC-treated wild-type DCs. In this article, we establish that GILZhi DCs display an accumulation of Foxp3+ Tregs in the spleens of young CD11c-GILZhi mice. In addition, we show that GILZhi 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 GILZhi 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 GILZhi 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 GILZhi 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.

Impact of immunosuppressive drugs on the therapeutic efficacy of ex vivo expanded human regulatory T cells

“…Human DCs treated with glucocorticoids up-regulate the GC-Induced Leucine Zipper protein (GILZ) and differentiate into tolerogenic cells capable of inducing IL-10-producing antigen-specific Tregs. 49 Finally, our data have shown that the in vivo administration of RAPA maintained the survival and proliferation of adoptively transferred Tregs. In contrast, the proliferation of non-Treg cells was inhibited.…”

GILZ regulates Th17 responses and restrains IL-17-mediated skin inflammation

“…Thus, GILZ promotes anti-inflammatory CD4 T cell responses; inhibiting Th17 and promoting induced regulatory T cell (iTreg) differentiation through its actions in T cells [45] and dendritic cells [12,46]. GILZ has also been described as a negative regulator of Th1-associated pathology [14] and we have previously found that GILZ inhibits IFNg expression in a delayed-type hypersensitivity model [16].…”

High‐dose dexamethasone or all‐trans‐retinoic acid restores the balance of macrophages towards M2 in immune thrombocytopenia

“…However, our data indicated that neither HD‐DXM‐modulated nor ATRA‐modulated M1 macrophages could generate Tr1 cells, probably because of the insufficiency of IL‐10, which, as has been shown, plays a central role in Tr1 induction . This finding was in accordance with the observations that either glucocorticoid or ATRA could prime DCs to induce the prduction of IL‐10 + Tr1 cells . Tr1 cells could then inhibit cytokine production and the stimulatory capacity of macrophages via secreting large amounts of IL‐10 .…”