Dendritic cell control of tolerogenic responses

Abstract

One of the most fundamental problems in immunology is the seemingly schizophrenic ability of the immune system to launch robust immunity against pathogens, while acquiring and maintaining a state of tolerance to the body's own tissues and the trillions of commensal microorganisms and food antigens that confront it every day. A fundamental role for the innate immune system, particularly dendritic cells (DCs), in orchestrating immunological tolerance has been appreciated, but emerging studies have highlighted the nature of the innate receptors and the signaling pathways that program DCs to a tolerogenic state. Furthermore, several studies have emphasized the major role played by cellular interactions and the microenvironment in programming tolerogenic DCs. Here, we review these studies and suggest that the innate control of tolerogenic responses can be viewed as different hierarchies of organization, in which DCs, their innate receptors and signaling networks, and their interactions with other cells and local microenvironments represent different levels of the hierarchy.

Fig. 1. Environmental stimuli and their receptors that program tolerogenic DCs

A broad range of stimuli including microbial components, tissue antigens (mannosylated antigens, glycoconjugate), and apoptotic cells interact with specific receptors on DCsand program DCs to a tolerogenic state. Various anti-inflammatory cytokines and immunosuppressive agents also programDCs to acquire tolerogenic properties and promotethe induction of IL-10, IDO, and TGF-β that are critical for promoting T-regulatory response, orinducethe expression cell surface molecule such as ILT3/4, PDL1/2, ICOS-L, B7.H, CD95L that promotes T-cell anergy or deletion.

Fig. 2. Signaling networks that program DCs to induce T-regulatory responses

(A) TLR-ERK-mediated induction of retinoic acid metabolizing enzymes and IL-10. Activation of DCs through TLR2/6 ligands leads to ERK activation, which mediates induction of Raldh2. Thisresults in the conversion of retinal to retinoic acid (RA), which then exerts an autocrine effect on DCsvia RAR or RXR to induce SOSC3. This thensuppresses activation of p38 MAPK and pro-inflammatory cytokines. Furthermore, IL-10 and RA programDCs to induce T-regulatory cell responses and limit theinflammatory responses. (B) β-catenin signaling pathways in programming regulatory DCs. Activation of β-catenin pathway by E-cadherine, TLRs, or wnt-ligands in DCs promotes induction of anti-inflammatory factors such vitamin A, IL-10, and TGF-β that are critical for promoting T-regulatory cell response and limiting inflammatory responses.

Fig. 3

Cell-cell cooperation in programming tolerogenic DCs.

Fig. 4. Tissue microenvironments condition DCs to induce T-regulatory responses

In the liver, hepatocytes, stellate cells, and Kupffer cells produce various anti-inflammatory factors such IL-10, RA, TGF-β, and PGE2 that condition DCs to a tolerogenic state. Furthermore, these DCs produce IL-10 and TGF-β to induceT-regulatory cells or produce IL-27 and PGE2 to induce T-cell anergy or apoptosis.