Sampling and signaling in plasmacytoid dendritic cells: the potential roles of Siglec-H

doi:10.1016/j.it.2006.04.005

Trends in Immunology

Volume 27, Issue 6, June 2006, Pages 255-260

https://doi.org/10.1016/j.it.2006.04.005 Get rights and content

Plasmacytoid dendritic cells (pDCs) detect viruses through toll-like receptor (TLR)7 and TLR9 and respond by secreting type I interferons (IFNs). Because TLR7 and TLR9 are present in endosomes, a mechanism is required to capture and deliver viruses to TLRs. A member of the sialic acid binding Ig-like lectin (Siglec) family, Siglec-H, has recently been identified as a specific surface marker for pDCs in mice. Siglec-H is endocytosed and can mediate the uptake of antigens for processing and presentation. Thus, Siglec-H might have a role in the capture of viruses or other pathogens for their delivery to intracellular TLRs. Paradoxically, Siglec-H also transmits intracellular signals through the associated adaptor DAP12, which reduces pDC responses to TLR ligands. In this review, we discuss models to explain the potential outcomes of Siglec-H engagement in the pDC secretion of type I IFN.

Section snippets

Plasmacytoid dendritic cells in immune responses

Plasmacytoid dendritic cells (pDCs) have an important role as the first responders to viruses. During viral infections, pDCs migrate from the blood to the infection site, where they secrete large amounts of type I interferon (IFN) (i.e. IFN-α and IFN-β), interleukin (IL)-12 and proinflammatory chemokines 1, 2. IFN-α and IFN-β induce cellular anti-viral responses, limiting the spread of viral infection. Moreover, IFN-α and IFN-β promote CD8⁺ T-cell and natural killer (NK)-cell cytotoxicity, T

Antigen capturing molecules on human pDCs

Human pDCs were originally identified as a small subset of lineage(CD3, CD14, CD16, CD19 and CD56)⁻CD11c⁻CD4⁺CD123^bright cells within peripheral blood and secondary lymphoid organs. The search for human pDC-specific markers led to the identification of a cell-surface transmembrane glycoprotein, blood dendritic-cell antigen (BDCA)-2, which enables pDCs to be easily identified in humans [13]. BDCA-2 is a C-type lectin receptor, suggesting that it might bind to carbohydrates associated with

Identification of Siglec-H on mouse pDCs

pDCs were identified in mouse as a subset of dendritic cells expressing low levels of CD11c and the markers Ly6C, B220, as well as varying levels of CD8α, but that lacked CD11b 27, 28, 29. This complex phenotype of mouse pDCs made them difficult to identify, requiring the use of three to four markers to distinguish them from other cell types. Four antibodies were subsequently generated that specifically recognized mouse pDC-restricted surface antigens: 120G8 [30], 440c [31], mPDCA1 [32] and

Structural and evolutionary features of Siglec-H

Siglecs are type I transmembrane proteins that bind to sialic acids decorating a variety of cell-surface glycoproteins 40, 41. Structurally, Siglecs belong to the immunoglobulin superfamily; their extracellular regions consist of an N-terminal V-type Ig-like domain, which binds to sialic acid, followed by one to sixteen C2-type Ig-like domains. Two groups of Siglecs have been defined: the first group includes sialoadhesin (Siglec-1), CD22 (Siglec-2) and MAG (Siglec-4); these Siglecs are

The potential of Siglec-H as an antigen-capturing molecule

Recently, Zhang et al. showed that Siglec-H can function as an endocytic receptor, mediating antigen uptake and presentation to T cells [38]. Anti-Siglec-H antibodies are internalized and delivered to the endosomal–lysosomal compartment. Moreover, ovalbumin conjugated with anti-Siglec-H antibodies is captured, processed and the resulting peptides are cross-presented onto MHC class I molecules, promoting the expansion of ovalbumin-specific CD8⁺ T cells in vivo. These data indicate that Siglec-H

The paradoxical inhibitory function of Siglec-H

CD33 and CD33-related molecules characterized to date contain cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs) or ITIM-like motifs and function as inhibitory receptors 40, 41. ITIMs recruit the SH2-domain-containing protein tyrosine phosphatases SHP-1 and/or SHP-2, which inhibit cell activation by dephosphorylating a variety of intracellular effector molecules [47]. By contrast, Siglec-H contains no signaling motifs in its short cytoplasmic domain and associates with the

Future perspective

The specificity of Siglec-H for pDCs and its expression in macrophages and brain requires further investigation. Nevertheless, Siglec-H remains the best cell-surface marker in mice for identifying pDCs in all organs except the brain. Siglec-H might function in the uptake of viruses or other pathogens facilitating their delivery into TLR- and MHC-containing endosomal compartments. It will be important to identify the exogenous and endogenous ligands of Siglec-H. Furthermore, studies of the

Acknowledgements

We thank Julia Klesney-Tait, Isaiah Turnbull, Winifried Barchet, Daved Fremont and the referee for helpful suggestions and critiques. M.C. is supported by NIH grant R01CA109 673-01A1 and A.L.B. by Infectious Diseases Training grant 2T32A10717226.

References (57)

C.A. Biron
Interferons α and β as immune regulators – a new look
Immunity
(2001)
G. Jego
Plasmacytoid dendritic cells induce plasma cell differentiation through type I interferon and interleukin 6
Immunity
(2003)
J.F. Fonteneau
Activation of influenza virus-specific CD4⁺ and CD8⁺ T cells: a new role for plasmacytoid dendritic cells in adaptive immunity
Blood
(2003)
G. Schlecht
Murine plasmacytoid dendritic cells induce effector/memory CD8⁺ T-cell responses in vivo after viral stimulation
Blood
(2004)
A. Dzionek
Plasmacytoid dendritic cells: from specific surface markers to specific cellular functions
Hum. Immunol.
(2002)
N. Novak
Characterization of FcεRI-bearing CD123⁺ blood dendritic cell antigen-2⁺ plasmacytoid dendritic cells in atopic dermatitis
J. Allergy Clin. Immunol.
(2004)
B. Foster
Human dendritic cell 1 and dendritic cell 2 subsets express FcεRI: correlation with serum IgE and allergic asthma
J. Allergy Clin. Immunol.
(2003)
K. Lock
Expression of CD33-related siglecs on human mononuclear phagocytes, monocyte-derived dendritic cells and plasmacytoid dendritic cells
Immunobiology
(2004)
P. Bjorck
Isolation and characterization of plasmacytoid dendritic cells from Flt3 ligand and granulocyte-macrophage colony-stimulating factor-treated mice
Blood
(2001)
A. Blasius
A cell-surface molecule selectively expressed on murine natural interferon-producing cells that blocks secretion of interferon-α
Blood
(2004)

A. Krug

TLR9-dependent recognition of MCMV by IPC and DC generates coordinated cytokine responses that activate antiviral NK cell function

Immunity

(2004)

Y. Kamogawa-Schifter

Ly49Q defines 2 pDC subsets in mice

Blood

(2005)

A.L. Blasius

Siglec-H is an IPC-specific receptor that modulates type I IFN secretion through DAP12

Blood

(2006)

P.R. Crocker

Siglecs in innate immunity

Curr. Opin. Pharmacol.

(2005)

M.S. Alphey

High resolution crystal structures of Siglec-7. Insights into ligand specificity in the Siglec family

J. Biol. Chem.

(2003)

A.P. May

Crystal structure of the N-terminal domain of sialoadhesin in complex with 3′ sialyllactose at 1.85 Å resolution

Mol. Cell

(1998)

Y. Kumamoto

Identification of sialoadhesin as a dominant lymph node counter-receptor for mouse macrophage galactose-type C-type lectin 1

J. Biol. Chem.

(2004)

A. Fuchs

Paradoxic inhibition of human natural interferon-producing cells by the activating receptor NKp44

Blood

(2005)

D.S. Green

IgG-derived Fc down-regulates virus-induced plasmacytoid dendritic cell (pDC) IFNα production

Cytokine

(2004)

B. Pasquier

Identification of FcαRI as an inhibitory receptor that controls inflammation: dual role of FcRγ ITAM

Immunity

(2005)

E. Savarese

U1 small nuclear ribonucleoprotein immune complexes induce type I interferon in plasmacytoid dendritic cells via TLR7

Blood

(2006)

A.B. Bakker

DAP12-deficient mice fail to develop autoimmunity due to impaired antigen priming

Immunity

(2000)

E. Tomasello

Combined natural killer cell and dendritic cell functional deficiency in KARAP/DAP12 loss-of-function mutant mice

Immunity

(2000)

M. Colonna

Plasmacytoid dendritic cells in immunity

Nat. Immunol.

(2004)

Y.J. Liu

IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors

Annu. Rev. Immunol.

(2005)

M. Dalod

Interferon α/β and interleukin 12 responses to viral infections: pathways regulating dendritic cell cytokine expression in vivo

J. Exp. Med.

(2002)

S.M. Santini

Type I interferon as a powerful adjuvant for monocyte-derived dendritic cell development and activity in vitro and in Hu-PBL-SCID mice

J. Exp. Med.

(2000)

A. Krug

Interferon-producing cells fail to induce proliferation of naive T cells but can promote expansion and T helper 1 differentiation of antigen-experienced unpolarized T cells

J. Exp. Med.

(2003)

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Trends in Immunology

Sampling and signaling in plasmacytoid dendritic cells: the potential roles of Siglec-H

Section snippets

Plasmacytoid dendritic cells in immune responses

Antigen capturing molecules on human pDCs

Identification of Siglec-H on mouse pDCs

Structural and evolutionary features of Siglec-H

The potential of Siglec-H as an antigen-capturing molecule

The paradoxical inhibitory function of Siglec-H

Future perspective

Acknowledgements

Immunity

Immunity

Blood

Blood

Hum. Immunol.

J. Allergy Clin. Immunol.

J. Allergy Clin. Immunol.

Immunobiology

Blood

Blood

Immunity

Blood

Blood

Curr. Opin. Pharmacol.

J. Biol. Chem.

Mol. Cell

J. Biol. Chem.

Blood

Cytokine

Immunity

Blood

Immunity

Immunity

Plasmacytoid dendritic cells in immunity

Nat. Immunol.

IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors

Annu. Rev. Immunol.

Interferon α/β and interleukin 12 responses to viral infections: pathways regulating dendritic cell cytokine expression in vivo

J. Exp. Med.

Type I interferon as a powerful adjuvant for monocyte-derived dendritic cell development and activity in vitro and in Hu-PBL-SCID mice

J. Exp. Med.

Interferon-producing cells fail to induce proliferation of naive T cells but can promote expansion and T helper 1 differentiation of antigen-experienced unpolarized T cells

J. Exp. Med.