Activation of dendritic cells: translating innate into adaptive immunity

https://doi.org/10.1016/j.coi.2003.11.007Get rights and content

Abstract

Innate recognition of infection in vertebrates can lead to the induction of adaptive immune responses through activation of dendritic cells (DCs). DCs are activated directly by conserved pathogen molecules and indirectly by inflammatory mediators produced by other cell types that recognise such molecules. In addition, it is likely that DCs are activated by poorly characterised cellular stress molecules and by disturbances in the internal milieu. The multiplicity of innate pathways for DC activation may have evolved to ensure that any signs of infection are detected early, before overwhelming pathogen replication. Understanding which of these signs are both necessary and sufficient to convert DCs into the immunostimulatory antigen-presenting cells that prime appropriate effector T cells may hold the key to improved strategies for vaccination and immunotherapy.

Introduction

The adaptive immune system, found exclusively in vertebrates, evolved from an ancient innate defence mechanism common to all metazoans. Given this past, it is not surprising that adaptive immunity takes its cues from the innate immune system. Indeed, as postulated by Janeway [1], it is now abundantly clear that innate signalling precedes, and is essential for, the generation of T-cell and B-cell responses. Central to this process are the dendritic cells (DCs), a heterogeneous family of leukocytes that integrate innate information and convey it to lymphocytes. Innate stimulation of DCs can trigger their differentiation into immunogenic antigen-presenting cells (APCs) capable of priming and sustaining the expansion of naı̈ve T cells. In addition, DCs direct T-cell effector differentiation, thus being responsible for ensuring that the specificity of the innate immune system, which distinguishes between many classes of potential pathogens, is translated into an equally specific class of adaptive immune response. This review focuses on our emerging understanding of the mechanisms involved in innate activation of DCs and how they may impact on immunity.

Section snippets

Innate activation of dendritic cells

There are several distinct mechanisms leading to innate DC activation, all of which probably share an evolutionary link to infection [2]. In this review, a distinction is made between pattern recognition pathways, which allow direct or indirect detection of conserved molecular signatures of potential pathogens (the so-called ‘pathogen-associated molecular patterns’, or PAMPs; [1]), and PAMP-independent DC activation in response to self-molecules or alterations in the internal milieu (Figure 1).

Conclusions

Microbial components and inflammatory cytokines have long been known to profoundly affect DC phenotype and function. However, the pathways involved in infection sensing by DCs still remain elusive. Recent advances in our understanding of innate immunity, including the molecular identification of PRRs (e.g. TLRs) and sensors of altered self (e.g. NKG2D), and an increased awareness of the role of inflammatory cytokines in promoting acquired immunity (e.g. IFN-I), have opened the door to molecular

Update

Recent work has demonstrated that uric acid released from dying cells may act as a ‘danger’ signal that promotes cross-priming [46].

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

Acknowledgements

I am grateful to members of the Immunobiology Laboratory, Cancer Research UK, for discussions and critical review of the manuscript.

References (46)

  • C. Ruedl et al.

    CD8(+) T cells mediate CD40-independent maturation of dendritic cells in vivo

    J. Exp. Med.

    (1999)
  • S. Manickasingham et al.

    Microbial and T cell-derived stimuli regulate antigen presentation by dendritic cells in vivo

    J. Immunol.

    (2000)
  • E. Muraille et al.

    T cell-dependent maturation of dendritic cells in response to bacterial superantigens

    J. Immunol.

    (2002)
  • R.B. Mailliard et al.

    Complementary dendritic cell-activating function of CD8+ and CD4+ T cells: helper role of CD8+ T cells in the development of T helper type 1 responses

    J. Exp. Med.

    (2002)
  • Reis e Sousa C: Toll-Like receptors and dendritic cells: for whom the bug tolls. Semin Immunol 2004, in...
  • A. Krug et al.

    Toll-like receptor expression reveals CpG DNA as a unique microbial stimulus for plasmacytoid dendritic cells which synergizes with CD40 ligand to induce high amounts of IL-12

    Eur. J. Immunol.

    (2001)
  • D. Jarrossay et al.

    Specialization and complementarity in microbial molecule recognition by human myeloid and plasmacytoid dendritic cells

    Eur. J. Immunol.

    (2001)
  • N. Kadowaki et al.

    Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens

    J. Exp. Med.

    (2001)
  • N. Kadowaki et al.

    Distinct CpG DNA and polyinosinic-polycytidylic acid double-stranded RNA, respectively, stimulate CD11c− type 2 dendritic cell precursors and CD11c+ dendritic cells to produce type I IFN

    J. Immunol.

    (2001)
  • V. Hornung et al.

    Quantitative expression of toll-like receptor 1-10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides

    J. Immunol.

    (2002)
  • J. Lund et al.

    Toll-like receptor 9-mediated recognition of herpes simplex virus-2 by plasmacytoid dendritic cells

    J. Exp. Med.

    (2003)
  • M. Colonna et al.

    Interferon-producing cells: on the front line in immune responses against pathogens

    Curr. Opin. Immunol.

    (2002)
  • A.D. Edwards et al.

    Toll-like receptor expression in murine DC subsets: lack of TLR7 expression by CD8α+ DC correlates with unresponsiveness to imidazoquinolines

    Eur. J. Immunol.

    (2003)
  • Cited by (296)

    • Aging-induced fragility of the immune system

      2021, Journal of Theoretical Biology
    View all citing articles on Scopus
    View full text