Elsevier

Current Opinion in Immunology

Volume 14, Issue 6, 1 December 2002, Pages 765-770
Current Opinion in Immunology

Review
Dendritic cells: inciting and inhibiting autoimmunity

https://doi.org/10.1016/S0952-7915(02)00399-0Get rights and content

Abstract

Dendritic cells are considered the most influential antigen presenting cells in the body because of their unique role in initiating immunity against threatening antigens. Recent studies addressing the consequences of self-antigen presentation by dendritic cells revealed the unexpected ability of these antigen presenting cells to inhibit T cell-mediated autoimmune diseases. The specific mechanisms by which dendritic cells suppress immune responses have been explored during the past year. These efforts indicate that extrathymic dendritic cells control autoimmunity by inducing peripheral T cell tolerance, a function intimately linked to their state of maturation.

Introduction

Dendritic cells (DCs) are bone marrow-derived antigen presenting cells (APCs), unrivalled in their capacity for activating naı̈ve and effector T cells. The life history of DCs unfolds in two main developmental stages, termed immature and mature. Immature DCs form lattice-like networks in virtually every tissue where they peruse the extracellular milieu, avidly endocytosing diverse antigens. Signaling by select pathogens, pro-inflammatory mediators, or CD40L, triggers immature DCs to embark on an irreversible differentiation process that results in mature DCs displaying remarkable immunostimulatory might. Before reaching peak maturity, DCs pass through an intermediate stage that is obligatory for Langerhans cells (LCs), red pulp splenic DCs and bone marrow-derived DCs. At this stage, DCs exhibit a transitional or semi-mature phenotype in terms of TCR ligand and accessory molecule expression; however, their functional contributions have not been well characterized. Maturation radically boosts the immunogenicity of DCs by inducing the stable expression of peptide–MHC complexes, upregulation of costimulatory and adhesion molecules, secretion of chemokines and stimulatory cytokines, and swift migration to T cell zones of regional lymph nodes (LNs). As mature DCs are poised for the optimal stimulation of naı̈ve T lymphocytes [1], antigen presentation by mature DCs is a critical checkpoint in the generation of primary immune responses.

Central tolerance is an imperfect process, thereby allowing some autoreactive T lymphocytes to escape riddance in the thymus. DCs undoubtedly process self-proteins that are either expressed endogenously or acquired during endocytosis. DC presentation of self-antigens during infection or tissue injury could lead to the misguided generation of autoaggressive T lymphocytes. Despite the presence of autoreactive lymphocytes in the circulation and the presentation of self-epitopes by ‘nature's adjuvant’, most individuals escape the pathological consequences of autoimmunity. Thus, extrathymic mechanisms for subduing the autoreactive lymphocyte repertoire must exist. These elusive mechanisms are collectively referred to as peripheral tolerance. Emerging evidence indicates that DCs are responsible for the establishment of peripheral tolerance as well as immunity [2]. Genetic or environmental factors that alter the immunostimulatory capacity of DCs could impair peripheral tolerance induction leading to the onset of autoimmune disease.

The paradoxical ability of DCs to incite and inhibit autoimmune disease, as well as their features in autoimmune tissues, are reviewed here. Recent studies examining the specific mechanisms by which DCs induce peripheral tolerance are also discussed.

Section snippets

Dendritic cells provoke and prevent autoimmune disease

DCs are the only professional APCs capable of provoking autoimmune disease to date. The transfer of DCs, isolated from donors with acute autoimmune disease or propagated in vitro under conditions that induce maturation, generates a strong T helper (Th)-1 response, eventually culminating in autoimmune disease 3., 4., 5., 6., 7.. This ability is restricted to DCs that have been exposed to potent maturation stimuli in the presence of abundant self-antigen. In addition, chronic maturation of tissue

Elimination of autoreactive T lymphocytes

How do the same APCs that mount primary immune responses and precipitate autoimmunity also inhibit autoimmune disease? One possibility is that tolerance is mediated by immature or semi-mature DCs expressing low levels of T cell-receptor ligands and costimulatory molecules, whereas immunity is generated by mature DCs expressing high levels of these molecules. This would require the presentation of tissue antigens by immature DCs in secondary lymphoid tissue, a scenario that seems to conflict

Dendritic cell physiology in autoimmune tissues

Our understanding of the role of DCs in autoimmune disease stems, in part, from direct examination of these APCs in tissues of autoimmune subjects. DCs have been detected in lesions associated with numerous autoimmune diseases, including diabetes, rheumatoid arthritis (RA), psoriasis, EAE, thyroiditis, Sjogren's syndrome and SLE, and they are among the first cells to infiltrate target organs 37., 38., 39., 40., 41., 42., 43., 44.. Unique functions of DCs in autoimmune tissues may coordinate the

Conclusions

Our understanding of DCs and their roles in autoimmune disease has broadened in several ways this past year. We have learned that DCs not only promote immunity but also mediate peripheral T cell tolerance by direct elimination, T regulatory cell induction or counter-regulation. Tolerance can be induced by adoptive transfer of immature or semi-mature DCs, or by DCs presenting self-antigens under steady state conditions; however, the functional attributes that distinguish a tolerogenic from an

Update

A specific role has been identified for the enigmatic CD4+ DC population in controlling autoimmune disease. In contrast to their CD8+ counterparts, which trigger autoimmunity via robust IL-12 production, splenic CD4+ DCs reverse CNS homogenate-induced EAE [57••]. CD4+ DCs that have internalized aggregated Ig-MOG via FcγRI suppress autoimmunity by secreting IL-10.

Acknowledgements

I would like to thank Ananda Goldrath, Torben Lund, and Diane Mathis for critical assessment of the manuscript and stimulating discussions.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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