Molecular control of steady-state dendritic cell maturation and immune homeostasis

Abstract

Dendritic cells (DCs) are specialized sentinels responsible for coordinating adaptive immunity. This function is dependent upon coupled sensitivity to environmental signs of inflammation and infection to cellular maturation-the programmed alteration of DC phenotype and function to enhance immune cell activation. Although DCs are thus well equipped to respond to pathogens, maturation triggers are not unique to infection. Given that immune cells are exquisitely sensitive to the biological functions of DCs, we now appreciate that multiple layers of suppression are required to restrict the environmental sensitivity, cellular maturation, and even life span of DCs to prevent aberrant immune activation during the steady state. At the same time, steady-state DCs are not quiescent but rather perform key functions that support homeostasis of numerous cell types. Here we review these functions and molecular mechanisms of suppression that control steady-state DC maturation. Corruption of these steady-state operatives has diverse immunological consequences and pinpoints DCs as potent drivers of autoimmune and inflammatory disease.

Figure 1

Transcription factors Foxo3, T-bet, and NF-κB1 in dendritic cell (DC)–mediated control of immune homeostasis: upstream signals that control transcription factor activation and the resulting downstream transcription factor–mediated suppression and/or induction of DC responses. Foxo3 activation in DCs is induced by CTLA-4-B7 signals and possibly also by GM-CSF, metabolic or oxidative stress, and commensals (excluding TLR signals). Foxo3 activation includes post-translational modifications such as phosphorylation and acetylation, which induces its nuclear translocation and transcriptional functions. T-bet expression in DCs may be induced or regulated by commensals. Depicted are the functions of T-bet in DCs from T-bet^−/−/RAG2^−/− mice. The Cdcs1 locus regulates colitis susceptibility of T-bet^−/−/RAG2^−/− mice on a BALB/c or C57BL/6 genetic background. Whether T-bet directly regulates this locus is unknown. In the cytoplasm, full-length NF-κB1 (p105) enhances MAPK activation and sequesters other NF-κB subunits to prevent their activation. Proteolysis of p105 into p50 form is induced by IL-10, TLR signals, and potentially commensals. p50 homodimers are anti-inflammatory: They suppress TLR-induced inflammatory cytokines and also induce transcription of the anti-inflammatory cytokine IL-10. TLR signals also induce the activation of other NF-κB subunits (c-Rel, RelA, and RelB), which, when heterodimerized with p50, drive inflammatory cytokine gene transcription. pDCs are more dependent on p50 heterodimers for maturation and cytokine production than are cDCs or BMDCs. The relative contribution of p105, p50 homo- and heterodimers to the reduced cell number, aberrant functions, and increased potential of NF-κB1-deficient DCs to induce CD8⁺ T cell autoimmunity is unclear. (Abbreviations: Cdcs1, cytokine deficiency-induced colitis susceptibility-1; CTLA-4, cytotoxic T lymphocyte antigen 4; GM-CSF, granulocyte-macrophage colony-stimulating factor; IκBα, nuclear factor of kappa-light polypeptide gene enhancer in B cells inhibitor, alpha; TLR, Toll-like receptor; MAPK, mitogen-activated protein kinase.)

Figure 2

Steady-state cytokines, TAM receptor ligands, TLRs, and their signaling cascades in dendritic cell (DC) maturation: suppression and/or induction of DC responses and negative feedback regulation by SOCS proteins. IL-6 and IL-10 signals both induce STAT3 activation/phosphorylation and upregulation of SOCS proteins. Steady-state IL-6-STAT3 suppresses maturation of lymph node and liver DCs, whereas steady-state IL-10-STAT3 induces a broad-acting, potent, anti-inflammatory state that is critical to prevent colitis. IL-6 signals are more susceptible to negative regulation by SOCS3 than are IL-10 signals. Commensals and TLR ligands are upstream of steady-state IL-6 and IL-10 signals. IFN-γ, type I IFN, and TAM receptors all induce STAT1 activation/phosphorylation and SOCS protein expression. TAM receptor–mediated STAT1 activation is dependent upon association with and “hijacking” of the IFNAR-STAT1 signaling module (linked circles). Traditional IFNAR-STAT1 signals induce a proinflammatory response in addition to SOCS1 and SOCS3, which provide negative feedback regulation of IFNAR signals. TAM-IFNAR-STAT1 selectively induces SOCS1 and SOCS3, which negatively regulate TLR signals. SOCS1-deficient DCs and TAM receptor–deficient DCs induce overlapping perturbations to immune homeostasis, suggesting that IFN-γ, which drives disease mediated by SOCS1-deficient DCs, may regulate TAM receptor or TAM ligand expression. TAM receptors also transduce inhibitory signals upon recognition of apoptotic cells; these signals suppress subsequent TLR-induced responses. TLR-induced responses upregulate TAM receptors and the TAM ligand Gas6, providing an intrinsic mechanism for negative feedback regulation of TLR signals in DCs. (Abbreviations: IFNAR, IFN-α receptor; IFNGR, IFN-γ receptor; IRAK-M, IL-1 receptor-associated kinase M; IRF, interferon regulatory factor; SOCS, suppressor of cytokine signaling; STAT, signal transducer and activator of transcription; TLR, Toll-like receptor.)

Figure 3

Structure and functional domains of A20. The ovarian tumor (OTU) domain (red) and seven zinc fingers (Zfs) are shown. The cystine 103 and Zf4 motifs implicated in ubiquitin-modifying activity are indicated in yellow. Orange circles point to ubiquitin-binding motifs. A20 interacts with multiple other proteins, including other ubiquitin-binding proteins, ubiquitin-modifying enzymes, and kinases.