Plasmacytoid Dendritic Cells

Plasmacytoid dendritic cells (pDCs) are a subtype of dendritic cells (DCs) with the typical morphology of plasma cells that can be found in blood, lymphoid organs and tissues. They play a pivotal role in antiviral immunity by releasing vast amounts of type I interferon (IFN-I) in response to pathogen-derived nucleic acids.

Formation and Structure

The morphology of pDCs is very similar to plasma cells, with a rounded shape, an ex-centered nucleus, a basophilic cytoplasm, and a pale golgi called the acroplasm, but they are developmentally and functionally similar to dendritic cells.1 pDCs are derived from both myeloid and lymphoid progenitors and differentiate from pre-plasmacytoid DCs. They can further differentiate into fully developed dendritic cells.

Function

pDCs initiate the activation of an adaptive immune response to viruses and play a role in immunoregulation.2 They are highly effective at recognizing viruses or viral components via toll-like receptors (TLR7 and TLR9), and rapidly secrete large concentrations of antiviral IFN-I in response. Activated pDCs also have the potential to act as antigen-presenting cells by expressing high levels of major histocompatibility complex class II (MHC-II) and co-stimulatory molecules to activate T cells for an adaptive immune response, however this ability is not yet clearly understood.3,4

Role of Plasmacytoid Dendritic Cells in Health and Disease

Accumulating evidence has shown that pDCs can play an important role in many diseases – including autoimmune disorders and cancers – and could therefore be a potential target for therapeutic treatments. For example, chronic activation of pDCs and other dendritic cells by the body’s own DNA can contribute to the pathogenesis of systemic lupus erythematosus (SLE) by the hyperproduction of IFN-I.3 Similarly, the overproduction of IFN-I by pDCs can cause inflammation leading to the development of other autoimmune diseases, including psoriasis.5 In contrast, pDCs can infiltrate tumors in large numbers but produce no response to TLR stimulation, resulting in reduced or absent IFN-I production. Instead, pDCs promote the recruitment of regulatory T cells into the tumor environment, leading to immunosuppression and tumorigenesis.6 An extremely rare and aggressive form of leukemia that presents in the skin, blastic plasmacytoid dendritic cell neoplasm (BPDCN), is derived directly from pDCs.7

Emerging Research

Understanding the role of pDCs in mediating the pathogenesis of various diseases in human and mouse models is a well-established area of research. This research is positioning pDCs as important therapeutic candidates for diseases, including cancers and chronic inflammatory conditions, that result from abnormal IFN-I production, such as autoimmune pancreatitis.8

Tools to Study Plasmacytoid Dendritic Cells

Single-cell RNA sequencing provides an unbiased approach to classifying the unique transcriptomic information of cells to distinguish pDCs from other DC subtypes.9 Flow cytometry can also be used to distinguish pDCs from cDCs and other peripheral blood mononuclear cells through detection of relevant intracellular proteins or cytokines and cell-specific surface marker patterns.10

Cell Markers

Different cell markers can be used to study human and mouse-derived pDCs. In humans, they can be differentiated from conventional DCs with CD303, CD304, and CD123 and by CD45R, Ly-6C, mPDCA-1, Siglec-H and BST2 in mice.11 Murine and human cells both share the markers CD45RA, TLR7, and TLR9.12 In humans, pDCs can be distinguished from cDCs by their CD123+CD11c- phenotype. Expression of HLA-DR and costimulatory molecules CD80 and CD86 is common to both pDCs and cDCs. TLR1 and TLR2 can identify plasmacytoid predendritic cells.13

Overview of Specific Markers for pDCs
Human Cell Marker Alternative Names Location
CD45 Cell surface
CD45RA Cell surface
CD123 IL-3Rα Cell surface
CD223 LAG-3 Cell surface
CD287 TLR7 Cell surface
CD289 TLR9 Cell surface
CD303 BDCA2, CLEC4C Cell surface
CD304 Neuropilin 1, BDCA4 Cell surface

References

1. Soumelis, V. and Liu, Y.-J. (2006), From plasmacytoid to dendritic cell: Morphological and functional switches during plasmacytoid pre-dendritic cell differentiation. Eur. J. Immunol., 36: 2286-2292. https://onlinelibrary.wiley.com

2. Leylek R, Idoyaga J. (2019). The versatile plasmacytoid dendritic cell: Function, heterogeneity, and plasticity. International Review of Cell Molecular Biology. 349:177-211. https://www.sciencedirect.com

3. Li S, Wu J, Zhu S, Liu Y-J and Chen J. (2017). Disease-Associated Plasmacytoid Dendritic Cells. Frontiers in Immunology. 8:1268. https://www.frontiersin.org

4. Zanna, M.Y., Yasmin, A.R., et al. (2021). Review of dendritic cells, their role in clinical immunology, and distribution in various animal species. International Journal of Molecular Sciences, 22(15), p.8044.

5. Lande, R., Gregorio, J., Facchinetti, V. et al. (2007). Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature. 449, 564–569. https://www.nature.com

6. Zhou B, Lawrence T, Liang Y. (2021). The Role of Plasmacytoid Dendritic Cells in Cancers. Frontiers in Immunology. 12:749190. https://www.frontiersin.org PMID: 34737750; PMCID: PMC8560733

7. Sapienza, M. R., Pileri, A., et al. (2019). Blastic Plasmacytoid Dendritic Cell Neoplasm: State of the Art and Prospects. Cancers, 11(5), 595. https://www.mdpi.com

8. Renosi, F, Roggy, A., et al (2021) Transcriptomic and genomic heterogeneity in blastic plasmacytoid dendritic cell neoplasms: from ontogeny to oncogenesis. Blood Advances. 5 (5): 1540–1551. https://ashpublications.org

9. Karnell, J. L., Wu, Y., et al. (2021). Depleting plasmacytoid dendritic cells reduces local type I interferon responses and disease activity in patients with cutaneous lupus. Science Translational Medicine, 13(595).

10. Olshalsky SL, Fitzgerald-Bocarsly P. (2005) Flow cytometric techniques for studying plasmacytoid dendritic cells in mixed populations. Methods in Molecular Medicine. 116:183-94. https://link.springer.com PMID: 16000862

11. Musumeci, A., Lutz, K., Winheim, E,. & Krug, AB. (2019). What Makes a pDC: Recent Advances in Understanding Plasmacytoid DC Development and Heterogeneity. Frontiers in Immunology. 10:1222. https://www.frontiersin.org

12. Amon, L., Lehmann, C. H., Baranska, A., Schoen, J., Heger, L., & Dudziak, D. (2019). Transcriptional control of dendritic cell development and functions. International review of cell and molecular biology, 349, 55-151.

13. Raieli, S., Trichot, C., Korniotis, S., Pattarini, L., & Soumelis, V. (2019). TLR1/2 orchestrate human plasmacytoid predendritic cell response to gram+ bacteria. PLoS biology, 17(4), e3000209.

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