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The role of dendritic cells in autoimmunity

Key Points

  • Dendritic cells (DCs) show extensive subset heterogeneity and functional diversity, and the major functional DC subsets are conserved between humans and mice.

  • DCs contribute to both central and peripheral tolerance, but are not strictly required for either. A mere change in DC numbers, including after constitutive DC ablation, does not cause overt autoimmunity per se.

  • Aberrant activation of DCs is sufficient to cause autoimmunity and/or chronic inflammation. Multiple negative regulators prevent DC activation and autoimmunity in a cell-intrinsic manner.

  • DCs promote the priming and effector differentiation of self-reactive T cells in several experimental autoimmune diseases, including type 1 diabetes and experimental autoimmune encephalomyelitis (EAE).

  • Conversely, antigen presentation by DCs can promote regulatory T cell induction and reduce inflammation in some models, including in EAE.

  • The secretion of type I interferon by plasmacytoid DCs in response to self-nucleic acid might be a common mechanism that leads to pathogenesis in several autoimmune diseases, including in psoriasis, type 1 diabetes and systemic lupus erythematosus.

Abstract

Dendritic cells (DCs) initiate and shape both the innate and adaptive immune responses. Accordingly, recent evidence from clinical studies and experimental models implicates DCs in the pathogenesis of most autoimmune diseases. However, fundamental questions remain unanswered concerning the actual roles of DCs in autoimmunity, both in general and, in particular, in specific diseases. In this Review, we discuss the proposed roles of DCs in immunological tolerance, the effect of the gain or loss of DCs on autoimmunity and DC-intrinsic molecular regulators that help to prevent the development of autoimmunity. We also review the emerging roles of DCs in several autoimmune diseases, including autoimmune myocarditis, multiple sclerosis, psoriasis, type 1 diabetes and systemic lupus erythematosus.

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Figure 1: Potential roles of DCs in autoreactive T cell responses.
Figure 2: The production of type I IFN by pDCs as a common mechanism of pathogenesis.

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Acknowledgements

The authors thank M. Anderson and A. Ma for communicating unpublished results. The authors apologize to many colleagues whose studies could not be cited because of space constraints. B.R. has been supported by the Lupus Research Institute, the New York State Department of Health IDEA award N09G-22 and the US National Institutes of Health grant AI072571; V.S. has been supported by the Cancer Research Institute; D.G. has been supported by the S.L.E. Lupus Foundation, USA; and S.H. has been supported by the Swiss National Science Foundation.

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Glossary

Type I interferon

(Type I IFN). A family of cytokines that comprises IFNβ and multiple subtypes of IFNα, which all signal through a common IFNα/β receptor (IFNAR). Type I IFNs are typically induced by viral infection and can confer an antiviral state, growth arrest and/or apoptosis in host cells, as well as being able to recruit and to activate multiple immune cell types.

Cross-presentation

The ability of certain antigen-presenting cells to load peptides that are derived from exogenous antigens on MHC class I molecules. This property is uncommon, as most cells exclusively present peptides from their endogenous proteins on MHC class I molecules. Cross-presentation is essential for the initiation of immune responses to viruses that do not infect antigen-presenting cells.

DC ablation

The process by which denditic cells (DCs) are depleted; for example, using diphtheria toxin expression or administration. Diphtheria toxin or the diphtheria toxin receptor can be specifically expressed in DCs, which facilitates constitutive or diphtheria toxin-inducible DC ablation, respectively. Limitations to this method include the potential depletion of other cell types, the nonspecific toxicity of the administered diphtheria toxin and secondary effects owing to substantial cell death.

FMS-related tyrosine kinase 3 ligand

(FLT3L). An important growth factor in dendritic cell (DC) development. Its receptor FLT3 is expressed on haematopoietic progenitor cells as well as on all DCs, and FLT3L administration causes uneven expansion of most DC subsets.

Type 1 diabetes

(T1D; also known as insulin-dependent or juvenile diabetes). A disease that arises in children and young adults and that is caused by the destruction of pancreatic insulin-producing β-islet cells. It is thought that β-islet cell destruction is mediated by CD4+ and CD8+ T cells that are specific to β-islet cell autoantigens, such as insulin, zinc transporter 8 (ZNT8), islet-specific glucose-6-phospatase catalytic subunit-related protein (IGRP) and chromogranin A. Inbred non-obese diabetic (NOD) mice represent an excellent spontaneous model of T1D, a disease which is controlled by multiple genetic loci.

Systemic lupus erythematosus

(SLE). A disease characterized by the production of autoantibodies against self-DNA, chromatin, and RNA-associated proteins. The resulting immune complexes are deposited and induce inflammation in multiple tissues, particularly in kidney glomeruli (glomerulonephritis). Mouse models of spontaneous SLE include: the NZB/NZW strain and its derivative strains; MRL–FasLpr mice with a mutation in the death receptor CD95; and models with overexpression of Toll-like receptor 7 (TLR7; for example, Yaa locus-containing strains and Tlr7-transgenic mice).

Autoimmune myocarditis

A form of heart inflammation that is commonly associated with dilated cardiomyopathy, which is the most common cause of heart failure in young adults. It can be modelled in mice with experimental autoimmune myocarditis (EAM), which is induced by immunization with cardiac proteins such as the α-myosin heavy chain.

Multiple sclerosis

A disease that is most frequent in young female adults as a relapsing-remitting disease. It involves inflammation and focal neurodegeneration of the white matter of the central nervous system, which results from an autoimmune response to the components of the myelin sheath.

Experimental autoimmune encephalomyelitis

(EAE). A classical induced model of multiple sclerosis. EAE can be either actively induced by immunization against proteins of the myelin sheath, or passively induced by the adoptive transfer of encephalitogenic T helper cells. Transgenic models of EAE expressing myelin-specific T cell receptors are also widely studied.

Psoriasis

A chronic inflammation of the skin that is characterized by vascular hyperplasia and keratinocyte hyperproliferation, and is accompanied by a local pro-inflammatory milieu and immune cell infiltration. Mouse models typically recapitulate only some aspects of the disease and include genetic manipulation or chemical activation of immune responses (for example, with the Toll-like receptor 7 agonist imiquimod).

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Ganguly, D., Haak, S., Sisirak, V. et al. The role of dendritic cells in autoimmunity. Nat Rev Immunol 13, 566–577 (2013). https://doi.org/10.1038/nri3477

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