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Dendritic-cell control of pathogen-driven T-cell polarization

Key Points

  • Pathogens initiate adaptive immunity by activating immature dendritic cells (DCs) that mature into immuno-stimulatory effector cells and provide naive T cells with first, antigen that stimulates T cells with relevant T-cell receptors (TCRs); second, co-stimulation, which prevents the development of tolerance; and third, polarizing signals that determine the class of immune response.

  • Pathogens express pathogen-associated molecular patterns (PAMPs) that activate DCs directly through the ligation of pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs). In addition, pathogens activate DCs indirectly, through factors that these pathogens induce by activating neighbouring cells in the infected tissue by the same PAMP–PRR principle.

  • Certain pathogens can evade adaptive immunity by binding to receptors that initiate negative signals, which results in the inhibition of DC maturation and/or their expression of T-cell inhibitory molecules, both resulting in the development of anergic or regulatory T cells.

  • In contrast to the original belief, DCs are essentially flexible and can adopt mature T helper 1 (TH1)-, (TH2)- or regulatory T-cell-promoting phenotypes, instructed by the priming signals from microbial and tissue-derived factors.

  • PAMPs and tissue factors can be classified as type 1, type 2 and regulatory type, that programme (polarize) immature DCs to become mature effector DCs that selectively express T-cell-polarizing signals that promote the development of TH1, TH2 or regulatory T cells, respectively.

  • Although most TLRs mediate the polarization of TH1-cell-inducing DCs with variable efficacy, the PRRs that mediate TH2-cell-inducing DCs remain ill-defined. In addition, some PRRs, including TLR2, can mediate negative signals and promote the development of regulatory DCs.

  • DCs are heterogeneous and might differ in their ability to recognize PAMPs. In addition, some DC subsets have a fixed capacity to induce the development of regulatory T cells. The significance of the DC heterogeneity and the fixed T-cell-polarizing capacity remains to be established.

Abstract

Dendritic cells (DCs) are central in the orchestration of the various forms of immunity and tolerance. Their immunoregulatory role mainly relies on the ligation of specific receptors that initiate and modulate DC maturation resulting in the development of functionally different effector DC subsets that selectively promote T helper 1 (TH1)-, TH2- or regulatory T-cell responses. These DC-priming receptors include pattern recognition receptors (PRRs), which discriminate between (groups of) pathogens, as well as receptors that bind tissue factors that are produced either constitutively or in response to infection with pathogens, and characterize the type of tissue and the pathogen-specific response pattern of this tissue. Although it is becoming increasingly clear that the selective development of T-cell-polarizing DC subsets is related to the ligation of particular receptors that are involved in DC maturation, several inconsistencies with this concept remain.

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Figure 1: T-cell stimulation and T helper 1 (TH1)/TH2-cell polarization require three dendritic cell-derived signals.
Figure 2: Dendritic-cell polarization is influenced by the type of microorganism that is recognised and the site of activation.

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Acknowledgements

I thank H. Smits, E. de Jong, P. Kalinski and E. Wierenga for helpful discussions and the reviewers for their invaluable comments.

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DATABASES

LocusLink

CCL2

CCR7

CD4

CD11c

CD40

CD40L

dectin-1

ICAM1

IFN-α

IFN-β

IFN-γ

IL-10

IL-12

IL-18

IL-23

IL-27

IRF3

MYD88

OX40L

STAT4

TGF-β

TICAM1

TIRAP

TLR1

TLR2

TLR3

TLR4

TLR5

TLR6

TLR7

TLR9

TSLP

Glossary

TYPE 1 INTERFERONS

(Type 1 IFNs). The various forms of IFN-α and IFN-β.

NATURAL REGULATORY T CELLS

Thymus-derived CD4+CD25+ regulatory T cells that block immune cells through physical contact.

ADAPTIVE REGULATORY T CELLS

Regulatory T cells induced in the periphery that block immune cells through the production of cytokines.

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Kapsenberg, M. Dendritic-cell control of pathogen-driven T-cell polarization. Nat Rev Immunol 3, 984–993 (2003). https://doi.org/10.1038/nri1246

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