Glucocorticoid-Induced Leucine Zipper: Fine-Tuning of Dendritic Cells Function

Abstract

Dendritic cells (DCs) are key antigen-presenting cells that control the induction of both tolerance and immunity. Understanding the molecular mechanisms regulating DCs commitment toward a regulatory- or effector-inducing profile is critical for better designing prophylactic and therapeutic approaches. Initially identified in dexamethasone-treated thymocytes, the glucocorticoid-induced leucine zipper (GILZ) protein has emerged as a critical factor mediating most, but not all, glucocorticoids effects in both non-immune and immune cells. This intracellular protein exerts pleiotropic effects through interactions with transcription factors and signaling proteins, thus modulating signal transduction and gene expression. GILZ has been reported to control the proliferation, survival, and differentiation of lymphocytes, while its expression confers anti-inflammatory phenotype to monocytes and macrophages. In the past twelve years, a growing set of data has also established that GILZ expression in DCs is a molecular switch controlling their T-cell-priming capacity. Here, after a brief presentation of GILZ isoforms and functions, we summarize current knowledge regarding GILZ expression and regulation in DCs, in both health and disease. We further present the functional consequences of GILZ expression on DCs capacity to prime effector or regulatory T-cell responses and highlight recent findings pointing to a broader role of GILZ in the fine tuning of antigen capture, processing, and presentation by DCs. Finally, we discuss future prospects regarding the possible roles for GILZ in the control of DCs function in the steady state and in the context of infections and chronic pathologies.

Keywords: TSC22D3; antigen presentation; dendritic cells; glucocorticoid-induced leucine zipper; regulatory T cells; tolerance.

Figure 1

Glucocorticoid-induced leucine zipper (GILZ) isoforms and partners. Five murine GILZ (m-GILZ) isoforms, namely m-GILZ 1–4 and long GILZ (m-Long GILZ) have been identified in mouse (13, 28), with different N-TER domains while m-GILZ1, 2, 4 and m-Long GILZ encompass conserved TSC, LZ, and PRR domains. RAF1 (37) and AP1 (33) interact with GILZ1 and presumably GILZ3 N-TER domain. RAS interacts with the TSC (blue) domain (38). LZ (gray) domain allows dimerization (33). Nuclear factor Kappa B interacts with the PRR (green) domain and requires an EAP motif in positions 121–123 of GILZ1 (39). Predicted posttranslational modification sites are annotated with their positions (^X) and the nature of the modification, i.e., phosphorylation, p; glycosylation, g; and sumoylation, s. Tsc22-d3 transcription starts either at a canonical AUG codon or at an upstream non-canonical AUG codon. GILZ isoforms derived from the use of the same codon display identical N-TER domain (orange or yellow, respectively). Protein sequences were aligned using BLAST. The scale is proportional to the real size of the protein. N-TER, N-terminal domain; TSC, TGF-β-stimulated clone; LZ, leucine zipper; PRR, proline-rich region.

Figure 2

Glucocorticoid-induced leucine zipper (GILZ) regulation and functions in dendritic cells (DCs). GILZ expression in DCs can be induced by steady-state factors (11, 21, 22), immunosuppressive cytokines like TGF-β or interleukin (IL)-10 (20, 25), DC-maturation cocktail containing TNF-α, IL-1β, IL-6, and PGE2 (24), cell-derived factors (26, 45, 67), immunosuppressive drugs as synthetic GCs, rapamycin, and mitomycine C (11), fungal proteases (68), and cancer microenvironment (26). So far, the only exogenous GILZ repressor reported in DCs is LPS (26, 27). In addition, GILZ levels are reduced in blood DCs from respiratory allergic patients (21). DC-SCRIPT acts as an endogenous GR-repressor, thus limiting GILZ induction upon GCs exposure (64, 65). High GILZ levels promote PD-L1 expression and IL-10 production while limiting IL-12 and IL-23 secretion. Thus, GILZ^hi DCs are poor inducers of Th1 and Th17 T cells but efficient Treg and Tr1 activators (20, 23, 25). GILZ inhibits NF-κB functions upon interaction with p65 subunit (39, 46, 52). GILZ repression promotes macropinocytosis, likely upon increased p38-MAPK phosphorylation (27). GILZ deletion reduces antigen cross-presentation (27). GCs, glucocorticoids; TGF-β, transforming growth factor-β; IL-10, interleukin-10; HGF, hepatocyte growth factor; LPS, lipopolysaccharide; ICOS, inducible co-stimulator; Foxp3, Forkhead box p3; NF-κB, nuclear factor kappa B; CTLA4, cytotoxic T-lymphocyte-associated protein; Tr1, Type 1 regulatory T cells; Treg, regulatory T cells; p38-MAPK, p38 mitogen-activated protein kinase; GR, glucocorticoid receptor; cDC, conventional dendritic cell; tsc22d3, TGF-β-stimulated clone (TSC) 22 domain family protein 3.