Trends in Immunology
Sampling and signaling in plasmacytoid dendritic cells: the potential roles of Siglec-H
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+CD123bright 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.
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