Elsevier

Seminars in Immunology

Volume 16, Issue 1, February 2004, Pages 27-34
Seminars in Immunology

Toll-like receptors and dendritic cells: for whom the bug tolls

https://doi.org/10.1016/j.smim.2003.10.004Get rights and content

Abstract

Recognition of molecular signatures of potential pathogens via toll-like receptors (TLRs) activates dendritic cells (DC), leading to the initiation of adaptive immunity. TLR signalling in DC causes an increase in display of MHC peptide ligands for T cell recognition, upregulation of co-stimulatory molecules important for T cell clonal expansion and secretion of immunomodulatory cytokines, which direct T cell differentiation into effectors. Remarkably, ligation of distinct TLRs can trigger differential cytokine production in a single DC type or result in different cytokines in distinct DC sub-types. Studying the complexity of DC responses to TLR ligands illuminates the link between innate recognition and adaptive immunity, paving the way for improved vaccines and strategies to induce tolerance to autoantigens or allografis.

Introduction

In little more than 5 years since they were first discovered, toll-like receptors (TLRs) have emerged as critical players in immunity. TLRs fulfil the criteria postulated nearly 15 years ago by Janeway for “pattern-recognition receptors” (PRRs), germline-encoded proteins evolutionarily selected to recognise “pathogen-associated molecular patterns” (PAMPs) carried by potential invaders [1]. Indeed, whether pathogenic or not, viruses, bacteria, fungi, protozoa and, possibly, metazoan parasites (collectively termed “bugs”) have a vast number of molecular signatures, from proteins to nucleic acids, that can serve as ligands for one or more TLRs. Engagement of TLRs on innate effector cells such as macrophages (M∅) and neutrophils results in activation of microbicidal effector pathways and inflammation. In addition, as predicted by Janeway, TLR signalling activates antigen-presenting cells and leads to T cell priming and acquired immunity. The critical mediators of this process are dendritic cells (DC), a family of leukocytes that have evolved specifically to translate innate recognition into adaptive immunity. This review focuses on how TLR triggering can radically alter the ability of DC to interact with T cells, how different DC subsets respond to TLR ligands and how the study of the interplay between TLR and DC biology has promoted an increased understanding of both. It is assumed that the reader will have a basic understanding of TLR and DC biology which can be gathered from numerous excellent reviews on the two subjects (e.g., [2], [3]), as well as from reviews by others in this journal issue.

Section snippets

What TLRs tell us about DCs

The study of DC responses to TLR ligands and TLR repertoires of DC subsets has helped define the mechanisms and consequences of DC activation and has furthered our understanding of DC subset biology. These two areas are summarised below.

What DCs tell us about TLRs

The study of DC has shed much light into various aspects of TLR biology. In particular, DC have proven a fertile ground for the discovery of new TLR ligands and have helped reveal some of the intricacies of TLR signalling.

Perspectives

The discovery of TLRs has made it possible to begin to study the molecular basis of DC activation, greatly illuminating our understanding of DC biology. In turn, DC have revealed some novels aspect of TLR signalling and ligand recognition. To translate these advances into novel vaccines and immunotherapies, will require deeper understanding of the relative contribution of direct versus indirect activation of DC to immune regulation, how different DC respond differently to the same TLR ligand,

Acknowledgements

I am grateful to members of the Immunobiology Laboratory, Cancer Research UK, for discussions and critical review of the manuscript. I would like to dedicate this review to the memory of Charles A. Janeway Jr. whose prescience about the role of innate recognition in adaptive immunity has greatly influenced my research.

References (82)

  • J. Banchereau et al.

    Immunobiology of dendritic cells

    Annu. Rev. Immunol.

    (2000)
  • M. Cella et al.

    Inflammatory stimuli induce accumulation of MHC class II complexes on dendritic cells

    Nature

    (1997)
  • K. Inaba et al.

    The formation of immunogenic major histocompatibility complex class II- peptide ligands in lysosomal compartments of dendritic cells is regulated by inflammatory stimuli

    J. Exp. Med.

    (2000)
  • S. Manickasingham et al.

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

    J. Immunol.

    (2000)
  • L. Delamarre et al.

    Presentation of exogenous antigens on Major Histocompatibility Complex (MHC) class I and MHC class II molecules is differentially regulated during dendritic cell maturation

    J. Exp. Med.

    (2003)
  • S.K. Datta et al.

    A subset of Toll-like receptor ligands induces cross-presentation by bone marrow-derived dendritic cells

    J. Immunol.

    (2003)
  • K. Hoshino et al.

    Differential involvement of IFN-beta in Toll-like receptor-stimulated dendritic cell activation

    Int. Immunol.

    (2002)
  • S. Gallucci et al.

    Natural adjuvants: endogenous activators of dendritic cells

    Nat. Med.

    (1999)
  • F. Mattei et al.

    IL-15 is expressed by dendritic cells in response to type I IFN, double-stranded RNA, or lipopolysaccharide and promotes dendritic cell activation

    J. Immunol.

    (2001)
  • M.C. Lebre et al.

    Double-stranded RNA-exposed human keratinocytes promote Th1 responses by inducing a Type-1 polarized phenotype in dendritic cells: role of keratinocyte-derived tumor necrosis factor alpha, type I interferons, and interleukin-18

    J. Invest. Dermatol.

    (2003)
  • C. Pasare et al.

    Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells

    Science

    (2003)
  • T.C. Mitchell et al.

    Immunological adjuvants promote activated T cell survival via induction of Bcl-3

    Nat. Immunol.

    (2001)
  • F. Granucci et al.

    Early IL-2 production by mouse dendritic cells is the result of microbial-induced priming

    J. Immunol.

    (2003)
  • A.M. Krieg

    CpG motifs in bacterial DNA and their immune effects

    Annu. Rev. Immunol.

    (2002)
  • B. Pulendran et al.

    Lipopolysaccharides from distinct pathogens induce different classes of immune responses in vivo

    J. Immunol.

    (2001)
  • A.D. Edwards et al.

    Microbial recognition via toll-like receptor-dependent and -independent pathways determines the cytokine response of murine dendritic cell subsets to CD40 triggering

    J. Immunol.

    (2002)
  • 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)
  • H. Hemmi et al.

    The roles of Toll-like receptor 9, MyD88, and DNA-dependent protein kinase catalytic subunit in the effects of two distinct CpG DNAs on dendritic cell subsets

    J. Immunol.

    (2003)
  • J.D. Marshall et al.

    Identification of a novel CpG DNA class and motif that optimally stimulate B cell and plasmacytoid dendritic cell functions

    J. Leukoc. Biol.

    (2003)
  • L. Alexopoulou et al.

    Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3

    Nature

    (2001)
  • D.M. Underhill et al.

    The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens

    Nature

    (1999)
  • B.N. Gantner et al.

    Collaborative Induction of Inflammatory Responses by Dectin-1 and Toll-like Receptor 2

    J. Exp. Med.

    (2003)
  • H. Hemmi et al.

    Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway

    Nat. Immunol.

    (2002)
  • M. Jurk et al.

    Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848

    Nat. Immunol.

    (2002)
  • J. Lee et al.

    Molecular basis for the immunostimulatory activity of guanine nucleoside analogs: activation of Toll-like receptor 7

    Proc. Natl. Acad. Sci. U.S.A.

    (2003)
  • K. Shortman et al.

    Mouse and human dendritic cell subtypes

    Nat. Rev. Immunol.

    (2002)
  • M. Muzio et al.

    Differential expression and regulation of toll-like receptors (TLR) in human leukocytes: selective expression of TLR3 in dendritic cells

    J. Immunol.

    (2000)
  • A. Visintin et al.

    Regulation of ToH-like receptors in human monocytes and dendritic cells

    J. Immunol.

    (2001)
  • T.K. Means et al.

    The Toll-like receptor 5 stimulus bacterial flagellin induces maturation and chemokine production in human dendritic cells

    J. Immunol.

    (2003)
  • 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)

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