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DC-SIGN: escape mechanism for pathogens

Key Points

  • Dendritic cells (DCs) express Toll-like receptors (TLRs) and C-type lectins that interact with pathogens.

  • C-type lectins interact with specific carbohydrate structures on pathogens to internalize pathogens for degradation in lysosomal compartments to enhance antigen processing and presentation.

  • TLRs recognize molecular patterns on pathogens that leads to DC activation, expression of co-stimulatory molecules and the production of inflammatory cytokines.

  • Different DC-subsets express different sets of TLRs and C-type lectins to orchestrate specific immune responses.

  • C-type lectins recognize self and non-self antigens, and can function as antigen receptors, adhesion receptors and signalling receptors. So far, only little is known about the antigen specificity of C-type lectins with the exception of the DC-specific C-type lectin DC-SIGN.

  • Cell- and tissue-specific glycosylation of a glycoprotein regulates the expression of carbohydrate residues and recognition by specific C-type lectins.

  • The C-type lectin DC-SIGN recognizes a wide variety of pathogens such as viruses, bacteria, yeast and parasites through the binding of mannose or Lewis-x carbohydrate structures.

  • DC-SIGN also functions as an adhesion receptor through binding of intercellular adhesion molecule 2 (ICAM2) and ICAM3.

  • Pathogens such as HIV-1 and Mycobacteria tuberculosis target DC-SIGN to escape immune surveillance.

  • HIV-1 targets DC-SIGN to hide in DCs and for efficient transmission to T cells, as DC-SIGN functions as a trans-receptor that efficiently presents infectious virus to target T cells.

  • Mycobacteria tuberculosis subverts DCs by targeting DC-SIGN, leading to altered signalling events that inhibit TLR signalling and suppress DC maturation.

  • The balance between TLRs and C-type lectins triggering by pathogens might be instrumental in the final immune response — immune activation or immune suppression.

Abstract

Dendritic cells (DCs) are crucial in the defence against pathogens. Invading pathogens are recognized by Toll-like receptors (TLRs) and receptors such as C-type lectins expressed on the surface of DCs. However, it is becoming evident that some pathogens, including viruses, such as HIV-1, and non-viral pathogens, such as Mycobacterium tuberculosis, subvert DC functions to escape immune surveillance by targeting the C-type lectin DC-SIGN (DC-specific intercellular adhesion molecule-grabbing nonintegrin). Notably, these pathogens misuse DC-SIGN by distinct mechanisms that either circumvent antigen processing or alter TLR-mediated signalling, skewing T-cell responses. This implies that adaptation of pathogens to target DC-SIGN might support pathogen survival.

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Figure 1: C-type lectins and Toll-like receptors: pathogen receptors on dendritic cells.
Figure 2: HIV-1 subverts intracellular processing by dendritic cells through DC-SIGN.
Figure 3: Mycobacteria tuberculosis target DC-SIGN through ManLAM to suppress cellular immune responses mediated by dendritic cells.
Figure 4: Model for C-type lectin and Toll-like receptor collaboration.

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Acknowledgements

We thank all former and present members of our group, including our collaborators whose work has helped shape the ideas. We thank A. Engering and S. van Vliet for critical reading of the manuscript. We are grateful to the Netherlands Organization for Scientific Research, the AIDS foundation, the Dutch stomach, kidney, liver organization and the Dutch Cancer Foundation for their financial support.

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Correspondence to Yvette van Kooyk.

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DATABASES

LocusLink

BDCA2

CCR5

CD205

CD206

CD207

CD209

CD4

CLEC1

DCAL1

DCIR

dectin-1

GM-CSF

gp120

ICAM2

ICAM3

IFN-γ

IL-4

IL-10

IL-12

LFA1

Nef

TLR2

TLR4

TLR6

TLR7

TLR9

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Consortium for functional glycomics

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van Kooyk, Y., Geijtenbeek, T. DC-SIGN: escape mechanism for pathogens. Nat Rev Immunol 3, 697–709 (2003). https://doi.org/10.1038/nri1182

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