Nuclear receptor signalling in dendritic cells connects lipids, the genome and immune function

Abstract

Dendritic cells (DCs) are sentinels of the immune system and represent a heterogeneous cell population. The existence of distinct DC subsets is due to their inherent plasticity and to the changing microenvironment modulating their immunological properties. Numerous signalling pathways have impacts on DCs. It appears that besides cytokines/chemokines, lipid mediators also have profound effects on the immunogenicity of DCs. Some of these lipid mediators exert an effect through nuclear hormone receptors. Interestingly, more recent findings suggest that DCs are able to convert precursors to active hormones, ligands for nuclear receptors. Some of these DC-derived lipids, in particular retinoic acid (RA), have a central function in shaping T-cell development and effector functions. In this review, we summarize and highlight the function of a set of nuclear receptors (PPARgamma, RA receptor, vitamin D receptor and glucocorticoid receptor) in DC biology. Defining the contribution of nuclear hormone receptor signalling in DCs can help one to understand the regulatory logic of lipid signalling and allow the exploitation of their potential for therapeutic intervention in various immunological diseases.

Figure 1

The immunological function of DCs. Differentiation and migration of tissue-resident DCs. DC precursors are bone marrow-derived cells that leave the blood vessel and reside in various tissues in the periphery (for example, epidermis, intestine or the vessel wall or the atherogenic plaque) as immature DCs. These cells are well armed for sampling antigens and can receive various cues from the surrounding tissues. Antigen uptake associated with ‘danger signals' leads to DC maturation and migration of draining lymph nodes. In the lymph nodes, mature DCs present antigens to naive T cells and activate them.

Figure 2

Effects of nuclear receptor agonists on the immunophenotype of DCs. Characteristic changes of cell surface markers and cytokine production on DCs on nuclear receptor activation. Here, we summarize the effects of PPARγ activators, retinoids, glucocorticoids and the active form of vitamin D on monocyte-derived DCs.

Figure 3

The chemical structures and conversion steps of three nuclear hormone receptor ligand precursors (vitamin A, cortisone and vitamin D) to the active compounds. Most of these chemical reactions can occur in DCs.

Figure 4

DC-produced nuclear receptor ligands modulate T-cell development and homing. Intestinal DCs produce the active form of vitamin A (retinoic acid). In contrast, skin DCs could secrete the active form of vitamin D (1,25 dihydroxy vitamin D3). Retinoic acid (RA) imprints gut-homing tropism of lymphocytes by inducing α4β7 integrin and CCR9 receptor; in addition, RA contributes to B-cell IgA production; moreover, this compound promotes FoxP3+ Treg cell differentiation but blocks Th17 T-cell development. 1,25 Dihydroxy vitamin D3 primes skin-homing tropism of T cells by inducing CCR10.