Plasmacytoid dendritic cell

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Plasmacytoid dendritic cells (pDCs) are a rare type of immune cell that are known to secrete large quantities of type 1 interferon (IFNs) in response to a viral infection. [1] They circulate in the blood and are found in peripheral lymphoid organs. They develop from bone marrow hematopoietic stem cells and constitute < 0.4% of peripheral blood mononuclear cells (PBMC). [2] [3] Other than conducting antiviral mechanisms, pDCs are considered to be key in linking the innate and adaptive immune systems. However, pDCs are also responsible for participating in and exacerbating certain autoimmune diseases like lupus. [4] pDCs that undergo malignant transformation cause a rare hematologic disorder, blastic plasmacytoid dendritic cell neoplasm. [5]

Contents

Development and characteristics

In the bone marrow, common dendritic cell progenitors expressing Flt3 (CD135) receptors are able to give rise to pDCs. Flt3 or CD135 signaling induces differentiation and proliferation of pDCs, although their mechanisms are not entirely understood. Phosphoinositide 3-kinase (PI3K)-dependent activation of mechanistic target of rapamycin (mTOR) is believed to regulate this signaling pathway. Transcription factor E2-2 has also been found to play a key role in influencing the lineage commitment of a common DC progenitor on its course to becoming a pDC. [6]

Unlike conventional dendritic cells (cDCs) that leave the bone marrow as precursors, pDCs leave the bone marrow to go to the lymphoid organs and peripheral blood upon completing development. Plasmacytoid dendritic cells are also distinguished from cDCs because of their ability to produce significant amounts of type-1 interferon. [7] pDC maturation is initiated when the cell comes in contact with a virus, prompting the upregulation of MHC class I and MHC class II, co-stimulatory molecules CD80, CD86, CD83, and c-c chemokine receptor 7 (CCR7) and interferon production gradually decreases. CCR7 expression prompts the matured pDC to migrate to a lymph node where it will be able to stimulate and interact with T cells. [8]

In humans, pDCs exhibit plasma cell morphology and express CD4, HLA-DR, CD123, blood-derived dendritic cell antigen-2 (BDCA-2), Toll-like receptor (TLR) 7 and TLR9 within endosomal compartments. Expression of TLR 7 and TLR 9 allows pDCs to interact with viral and host nucleic acids. TLR 7 and TLR 9 detect ssRNA and unmethylated CpG DNA sequences, respectively. [9] ILT7 and BDCA-4 are also expressed on human pDC surfaces, although their signaling pathways are still obscure. However, there are speculations that the interaction between ILT7 and BST2 may have a negative regulatory effect on the cell’s interferon production. [10] Unlike myeloid dendritic cells, myeloid antigens like CD11b, CD11c, CD13, CD14 and CD33 are not present on pDC surfaces. Furthermore, pDCs express markers CD123, CD303 (BDCA-2) and CD304 unlike other dendritic cell types. [11]

Blastic plasmacytoid dendritic cell neoplasm

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare type of myeloid cancer in which malignant pDCs infiltrate the skin, bone marrow, central nervous system, and other tissues. Typically, the disease presents with skin lesions (e.g. nodules, tumors, papules, bruise-like patches, and/or ulcers) that most often occur on the head, face, and upper torso. [5] This presentation may be accompanied by cPC infiltrations into other tissues to result in swollen lymph nodes, enlarged liver, enlarged spleen, symptoms of central nervous system dysfunction, and similar abnormalities in breasts, eyes, kidneys, lungs, gastrointestinal tract, bone, sinuses, ears, and/or testes. [12] The disease may also present as a pDC leukemia, i.e. increased levels of malignant pDC in blood (i.e. >2% of nucleated cells) and bone marrow and evidence (i.e. cytopenias) of bone marrow failure. [12] Blastic plasmacytoid dendritic cell neoplasm has a high rate of recurrence following initial treatments with various chemotherapy regimens. In consequence, the disease has a poor overall prognosis and newer chemotherapeutic and novel non-chemotherapeutic drug regimens to improve the situation are under study. [13]

Role in immunity

Upon stimulation and subsequent activation of TLR7 and TLR9, these cells produce large amounts (up to 1,000 times more than other cell type) of type I interferon (mainly IFN-α and IFN-β), which are critical anti-viral compounds mediating a wide range of effects and induce maturation of the pDC. For example, the secretion of type 1 interferon triggers natural killer cells to produce IFNγ while also activating the differentiation of B cells. [14] In addition, they can produce cytokines IL-12, IL-6 and TNF-α as well, helping to recruit other immune cells to the site of infection. [8]

Because they are capable of activating other immune cells, pDCs serve as a bridge between innate and adaptive immunity. A pDC's ability to stimulate T cells is heightened following maturation. As mentioned earlier, maturation also induces the expression of both MHC Class I and Class II molecules in pDCs as well, which allows the cell to optimize its antigen-presenting abilities. MHC class I on pDC surfaces are able to activate CD8+ T cells, while MHC class II have been found to activate CD4+ T cells. pDCs are also thought to be able to promote both T cell activation and tolerance. [7]

Role in autoimmunity and diseases

Psoriasis

Patients who suffer from psoriasis typically exhibit skin lesions where pDCs accumulate. Inhibiting pDCs from secreting IFN diminished the appearance of the skin lesions. When DNA is released via apoptosis of an infected host cell, antibodies are produced against the host's own DNA. (see autoantibody). These anti-host DNA antibodies are able to stimulate pDCs which proceed to secrete IFN, furthering the activity of adaptive immunity. [8]

Lupus

Although the pDC's ability to mass produce type 1 interferon can be effective in targeting a viral infection, it can also lead to Systemic lupus erythematosus if not regulated properly. Type 1 interferon production is strongly correlated with the progression of lupus, and is thought to drive excessive maturation of pDCs and activation of B cells, among many other effects. In patients with lupus, pDC levels in the circulating blood are decreased most of the pDCs have migrated toward the inflamed and affected tissues. [15]

HIV

The mass production of type 1 interferon may result in both positive and negative outcomes in response to HIV. Although type 1 interferon is efficient at facilitating maturation in pDCs and in killing infected T cells, excessive clearance of infected T cells may have detrimental effects and further weaken the patient's compromised immune system. [6] pDCs themselves can be infected by HIV but are also capable of sensing viral markers such as ssRNA and are impaired in their interferon-producing capacities. [16] However, it seems that in HIV, pDCs not only lose their interferon secreting properties but also die, expediting the progression of the disease. [17] Decreases in functional, live of uninfected pDCs have resulted in decreases in CD4+ T cells that further compromise the patient's immune defenses against HIV. Thus, maintaining balance and regulation of pDC activity is crucial for a more positive prognosis in HIV patients. [8]

COVID-19

Reduced numbers of pDCs with age is associated with increased COVID-19 severity, possibly because these cells are substantial interferon producers. [18]

Related Research Articles

<span class="mw-page-title-main">Interferon</span> Signaling proteins released by host cells in response to the presence of pathogens

Interferons are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten their anti-viral defenses.

<span class="mw-page-title-main">Dendritic cell</span> Accessory cell of the mammalian immune system

A dendritic cell (DC) is an antigen-presenting cell of the mammalian immune system. A DC's main function is to process antigen material and present it on the cell surface to the T cells of the immune system. They act as messengers between the innate and adaptive immune systems.

<span class="mw-page-title-main">T helper cell</span> Type of immune cell

The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considered essential in B cell antibody class switching, breaking cross-tolerance in dendritic cells, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages and neutrophils. CD4+ cells are mature Th cells that express the surface protein CD4. Genetic variation in regulatory elements expressed by CD4+ cells determines susceptibility to a broad class of autoimmune diseases.

<span class="mw-page-title-main">Natural killer cell</span> Type of cytotoxic lymphocyte

Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represent 5–20% of all circulating lymphocytes in humans. The role of NK cells is analogous to that of cytotoxic T cells in the vertebrate adaptive immune response. NK cells provide rapid responses to virus-infected cell and other intracellular pathogens acting at around 3 days after infection, and respond to tumor formation. Typically, immune cells detect the antigen presented on major histocompatibility complex (MHC) on infected cell surfaces, triggering cytokine release, causing the death of the infected cell by lysis or apoptosis. NK cells are unique, however, as they have the ability to recognize and kill stressed cells in the absence of antibodies and MHC, allowing for a much faster immune reaction. They were named "natural killers" because of the notion that they do not require activation to kill cells that are missing "self" markers of MHC class I. This role is especially important because harmful cells that are missing MHC I markers cannot be detected and destroyed by other immune cells, such as T lymphocyte cells.

Cross-presentation is the ability of certain professional antigen-presenting cells (mostly dendritic cells) to take up, process and present extracellular antigens with MHC class I molecules to CD8 T cells (cytotoxic T cells). Cross-priming, the result of this process, describes the stimulation of naive cytotoxic CD8+ T cells into activated cytotoxic CD8+ T cells. This process is necessary for immunity against most tumors and against viruses that infect dendritic cells and sabotage their presentation of virus antigens. Cross presentation is also required for the induction of cytotoxic immunity by vaccination with protein antigens, for example, tumour vaccination.

<span class="mw-page-title-main">Interferon regulatory factors</span> Protein family

Interferon regulatory factors (IRF) are proteins which regulate transcription of interferons. Interferon regulatory factors contain a conserved N-terminal region of about 120 amino acids, which folds into a structure that binds specifically to the IRF-element (IRF-E) motifs, which is located upstream of the interferon genes. Some viruses have evolved defense mechanisms that regulate and interfere with IRF functions to escape the host immune system. For instance, the remaining parts of the interferon regulatory factor sequence vary depending on the precise function of the protein. The Kaposi sarcoma herpesvirus, KSHV, is a cancer virus that encodes four different IRF-like genes; including vIRF1, which is a transforming oncoprotein that inhibits type 1 interferon activity. In addition, the expression of IRF genes is under epigenetic regulation by promoter DNA methylation.

<span class="mw-page-title-main">Interleukin 29</span> Protein-coding gene in the species Homo sapiens

Interleukin-29 (IL-29) is a cytokine and it belongs to type III interferons group, also termed interferons λ (IFN-λ). IL-29 plays an important role in the immune response against pathogenes and especially against viruses by mechanisms similar to type I interferons, but targeting primarily cells of epithelial origin and hepatocytes.

The type III interferon group is a group of anti-viral cytokines, that consists of four IFN-λ (lambda) molecules called IFN-λ1, IFN-λ2, IFN-λ3, and IFN-λ4. They were discovered in 2003. Their function is similar to that of type I interferons, but is less intense and serves mostly as a first-line defense against viruses in the epithelium.

<span class="mw-page-title-main">Interferon alpha-1</span> Protein-coding gene in the species Homo sapiens

Interferon alpha-1 is a protein that in humans is encoded by the IFNA1 gene.

<span class="mw-page-title-main">IFNA2</span> Mammalian protein found in Homo sapiens

Interferon alpha-2 is a protein that in humans is encoded by the IFNA2 gene.

<span class="mw-page-title-main">PRDM1</span> Protein-coding gene in the species Homo sapiens

PR domain zinc finger protein 1, or B lymphocyte-induced maturation protein-1 (BLIMP-1), is a protein in humans encoded by the gene PRDM1 located on chromosome 6q21. BLIMP-1 is considered a 'master regulator' of hematopoietic stem cells, and plays a critical role in the development of plasma B cells, T cells, dendritic cells (DCs), macrophages, and osteoclasts. Pattern Recognition Receptors (PRRs) can activate BLIMP-1, both as a direct target and through downstream activation. BLIMP-1 is a transcription factor that triggers expression of many downstream signaling cascades. As a fine-tuned and contextual rheostat of the immune system, BLIMP-1 up- or down-regulates immune responses depending on the precise scenarios. BLIMP-1 is highly expressed in exhausted T-cells – clones of dysfunctional T-cells with diminished functions due to chronic immune response against cancer, viral infections, or organ transplant.

<span class="mw-page-title-main">IRF8</span> Protein-coding gene in the species Homo sapiens

Interferon regulatory factor 8 (IRF8) also known as interferon consensus sequence-binding protein (ICSBP), is a protein that in humans is encoded by the IRF8 gene. IRF8 is a transcription factor that plays critical roles in the regulation of lineage commitment and in myeloid cell maturation including the decision for a common myeloid progenitor (CMP) to differentiate into a monocyte precursor cell.

Interleukin-28 receptor is a type II cytokine receptor found largely in epithelial cells. It binds type 3 interferons, interleukin-28 A, Interleukin-28B, interleukin 29 and interferon lambda 4. It consists of an α chain and shares a common β subunit with the interleukin-10 receptor. Binding to the interleukin-28 receptor, which is restricted to select cell types, is important for fighting infection. Binding of the type 3 interferons to the receptor results in activation of the JAK/STAT signaling pathway.

The following outline is provided as an overview of and topical guide to immunology:

<span class="mw-page-title-main">Blastic plasmacytoid dendritic cell neoplasm</span> Medical condition

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy. It was initially regarded as a form of lymphocyte-derived cutaneous lymphoma and alternatively named CD4+CD56+ hematodermic tumor, blastic NK cell lymphoma, and agranular CD4+ NK cell leukemia. Later, however, the disease was determined to be a malignancy of plasmacytoid dendritic cells rather than lymphocytes and therefore termed blastic plasmacytoid dendritic cell neoplasm. In 2016, the World Health Organization designated BPDCN to be in its own separate category within the myeloid class of neoplasms. It is estimated that BPDCN constitutes 0.44% of all hematological malignancies.

<span class="mw-page-title-main">IFNA16</span> Protein-coding gene in the species Homo sapiens

Interferon alpha-16, also known as IFN-alpha-16, is a protein that in humans is encoded by theIFNA16 gene.

Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of immune cells from the myeloid lineage.

The cGAS–STING pathway is a component of the innate immune system that functions to detect the presence of cytosolic DNA and, in response, trigger expression of inflammatory genes that can lead to senescence or to the activation of defense mechanisms. DNA is normally found in the nucleus of the cell. Localization of DNA to the cytosol is associated with tumorigenesis, viral infection, and invasion by some intracellular bacteria. The cGAS – STING pathway acts to detect cytosolic DNA and induce an immune response.

The dendritic cell-based cancer vaccine is an innovation in therapeutic strategy for cancer patients.

<span class="mw-page-title-main">Elina Zúñiga</span> Argentinian immunologist

Elina Zúñiga is an Argentinian Immunologist and Professor of Molecular Biology in the Division of Biological Sciences at the University of California, San Diego. Zúñiga has made critical discoveries regarding host-virus interactions in both acute and chronic infections. Using lymphocytic choriomeningitis models (LCMV) and murine cytomegalovirus models, her laboratory at UCSD studies host immune adaptations in chronic viral disease and methods of viral suppression of the immune system in order to develop novel methods and identify novel targets of anti-viral defence. In 2018, Zúñiga was chosen by the American Association of Immunologists to give the international Vanguard Lecture. Zúñiga is also co-founder of the Global Immunotalks series which she and Carla Rothlin started in 2020 as a means to make cutting-edge immunology research freely available and easily accessible to a global audience.

References

  1. ↑ Laustsen, Anders; van der Sluis, Renée M.; Gris-Oliver, Albert; Hernández, Sabina Sánchez; Cemalovic, Ena; Tang, Hai Q.; Pedersen, Lars Henning; Uldbjerg, Niels; Jakobsen, Martin R.; Bak, Rasmus O. (2021-09-02). "Ascorbic acid supports ex vivo generation of plasmacytoid dendritic cells from circulating hematopoietic stem cells". eLife. 10: e65528. doi: 10.7554/eLife.65528 . ISSN   2050-084X. PMC   8445615 . PMID   34473049.
  2. ↑ Laustsen, Anders; van der Sluis, Renée M.; Gris-Oliver, Albert; Hernández, Sabina Sánchez; Cemalovic, Ena; Tang, Hai Q.; Pedersen, Lars Henning; Uldbjerg, Niels; Jakobsen, Martin R.; Bak, Rasmus O. (2021-09-02). "Ascorbic acid supports ex vivo generation of plasmacytoid dendritic cells from circulating hematopoietic stem cells". eLife. 10: e65528. doi: 10.7554/eLife.65528 . ISSN   2050-084X. PMC   8445615 . PMID   34473049.
  3. ↑ Tversky JR, Le TV, Bieneman AP, Chichester KL, Hamilton RG, Schroeder JT (May 2008). "Human blood dendritic cells from allergic subjects have impaired capacity to produce interferon-alpha via Toll-like receptor 9". Clin. Exp. Allergy. 38 (5): 781–8. doi:10.1111/j.1365-2222.2008.02954.x. PMC   2707903 . PMID   18318750.
  4. ↑ Liu, Yong-Jun (April 2005). "IPC: Professional Type 1 Interferon-Producing Cells and Plasmacytoid Dendritic Cell Precursors". Annual Review of Immunology. 23 (1): 275–306. doi:10.1146/annurev.immunol.23.021704.115633. PMID   15771572.
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  7. 1 2 Villadangos, José A.; Young, Louise (September 2008). "Antigen-Presentation Properties of Plasmacytoid Dendritic Cells". Immunity. 29 (3): 352–361. doi: 10.1016/j.immuni.2008.09.002 . PMID   18799143.
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  9. ↑ Gill MA, Bajwa G, George TA, et al. (June 2010). "Counterregulation between the FcepsilonRI pathway and antiviral responses in human plasmacytoid dendritic cells". J. Immunol. 184 (11): 5999–6006. doi:10.4049/jimmunol.0901194. PMC   4820019 . PMID   20410486.
  10. ↑ Santana-de Anda, Karina; Gómez-Martín, Diana; Soto-Solís, Rodrigo; Alcocer-Varela, Jorge (August 2013). "Plasmacytoid dendritic cells: Key players in viral infections and autoimmune diseases". Seminars in Arthritis and Rheumatism. 43 (1): 131–136. doi:10.1016/j.semarthrit.2012.12.026. PMID   23462050.
  11. ↑ Collin, Matthew; McGovern, Naomi; Haniffa, Muzlifah (September 2013). "Human dendritic cell subsets". Immunology. 140 (1): 22–30. doi:10.1111/imm.12117. PMC   3809702 . PMID   23621371.
  12. 1 2 Kim MJ, Nasr A, Kabir B, de Nanassy J, Tang K, Menzies-Toman D, Johnston D, El Demellawy D (October 2017). "Pediatric Blastic Plasmacytoid Dendritic Cell Neoplasm: A Systematic Literature Review". Journal of Pediatric Hematology/Oncology. 39 (7): 528–537. doi:10.1097/MPH.0000000000000964. PMID   28906324. S2CID   11799428.
  13. ↑ Wang S, Wang X, Liu M, Bai O (April 2018). "Blastic plasmacytoid dendritic cell neoplasm: update on therapy especially novel agents". Annals of Hematology. 97 (4): 563–572. doi:10.1007/s00277-018-3259-z. PMID   29455234. S2CID   3627886.
  14. ↑ Getz, Godfrey S. (April 2005). "Bridging the innate and adaptive immune systems". Journal of Lipid Research. 46 (4): 619–622. doi:10.1194/jlr.E500002-JLR200. PMID   15722562.
  15. ↑ Chan, Vera Sau-Fong; Nie, Yin-Jie; Shen, Nan; Yan, Sheng; Mok, Mo-Yin; Lau, Chak-Sing (October 2012). "Distinct roles of myeloid and plasmacytoid dendritic cells in systemic lupus erythematosus". Autoimmunity Reviews. 11 (12): 890–897. doi:10.1016/j.autrev.2012.03.004. PMID   22503660.
  16. ↑ Pierog, Piotr; Zhao, Yanlin S. (November 2017). "Toxoplasma gondii Inactivates Human Plasmacytoid Dendritic Cells by Functional Mimicry of IL-10". Journal of Immunology. 200 (1): 186–195. doi: 10.4049/jimmunol.1701045 . PMC   7441501 . PMID   29180487.
  17. ↑ Fitzgerald-Bocarsly, Patricia; Jacobs, Evan S. (April 2010). "Plasmacytoid dendritic cells in HIV infection: striking a delicate balance". Journal of Leukocyte Biology. 87 (4): 609–620. doi:10.1189/jlb.0909635. PMC   2858309 . PMID   20145197.
  18. ↑ Bartleson JM, Radenkovic D, Verdin E (2021). "SARS-CoV-2, COVID-19 and the Ageing Immune System". Nature Aging . 1 (9): 769–782. doi:10.1038/s43587-021-00114-7. PMC   8570568 . PMID   34746804.
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