Human plasmacytoid dendritic cells elicit a Type I Interferon response by sensing DNA via the cGAS-STING signaling pathway

Plasmacytoid dendritic cells (pDCs) are innate immune cells able to produce large quantities of type I interferons (IFN) when activated. Human immunodeficiency virus (HIV)-infected patients show generalized immune dysfunction characterized in part by chronic interferon response. In this study we investigated the role of dendritic cells inactivating and maintaining this response. Specifically we compared the IFN geneactivity in pDCs in response to several viruses and TLR agonists. We hypothesized that 1) the pattern of IFN gene transcription would differ in pDCs treated with HIV than with other agents, and 2) that pDCs from patients from different stages of disease would respond differently to the stimulations. To test these hypotheses, we obtained pDCs from 15 HIV-infected and uninfected individuals and treated freshly isolated pDCs with either HIV (BAL strain), influenza virus (A/PR/8/34), Sendai virus (Cantell strain), TLR7 agonist(imiquimod), or TLR9 agonist (CpG-ODN) for 6h. Type I IFN gene transcription was monitored by real time qPCRfor IFNA1, A2, A5, A6, A8,A17, B1, and E1, and cytokine levels were assayed by Cytometric Bead Arrays forTNF?, IL6, IL8, IL10, IL1?, and IL12p70. pDC function as determined by these two assays showed no difference between HIV-infected and uninfected patients or between patients with early or chronic infection. Specifically, HIV did notinduce type I IFN gene expression, whereas influenza virus, Sendai virus and imiquimod did. Similarly, HIV failed to induce any cytokine release from pDCs in contrast to influenza virus, Sendai virus and imiquimod, which stimulatedrelease of TNF?, IL6, or IL8. Together these results suggest that the reaction of pDCs to HIV virus is quantitatively different from the response to agents such as virus, Sendai virus, and imiquimod. In addition, pDCs from HIV-infected persons have responses similar to pDCs from uninfected donors, suggesting, that the DC function may not be affected by HIV infection.

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Faculty Opinions recommendation of Toll-like receptor-mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI(3)K-mTOR-p70S6K pathway.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1123432.582895 ◽

2008 ◽

Author(s):

Adolfo Garcia-Sastre

Keyword(s):

Dendritic Cells ◽

Type I Interferon ◽

Plasmacytoid Dendritic Cells ◽

Type I ◽

Toll Like Receptor

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Type I Interferon Inhibition and Dendritic Cell Activation during Gammaherpesvirus Respiratory Infection

Journal of Virology ◽

10.1128/jvi.00360-07 ◽

2007 ◽

Vol 81 (18) ◽

pp. 9778-9789 ◽

Cited By ~ 24

Author(s):

Janet L. Weslow-Schmidt ◽

Nancy A. Jewell ◽

Sara E. Mertz ◽

J. Pedro Simas ◽

Joan E. Durbin ◽

...

Keyword(s):

Dendritic Cells ◽

Dendritic Cell ◽

Cell Activation ◽

Type I Interferon ◽

Plasmacytoid Dendritic Cells ◽

The Body ◽

Type I ◽

Type I Ifn ◽

Dendritic Cell Activation ◽

Murine Gammaherpesvirus

ABSTRACT The respiratory tract is a major mucosal site for microorganism entry into the body, and type I interferon (IFN) and dendritic cells constitute a first line of defense against viral infections. We have analyzed the interaction between a model DNA virus, plasmacytoid dendritic cells, and type I IFN during lung infection of mice. Our data show that murine gammaherpesvirus 68 (γHV68) inhibits type I IFN secretion by dendritic cells and that plasmacytoid dendritic cells are necessary for conventional dendritic cell maturation in response to γHV68. Following γHV68 intranasal inoculation, the local and systemic IFN-α/β response is below detectable levels, and plasmacytoid dendritic cells are activated and recruited into the lung with a tissue distribution that differs from that of conventional dendritic cells. Our results suggest that plasmacytoid dendritic cells and type I IFN have important but independent roles during the early response to a respiratory γHV68 infection. γHV68 infection inhibits type I IFN production by dendritic cells and is a poor inducer of IFN-α/β in vivo, which may serve as an immune evasion strategy.

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Human cytomegalovirus suppresses type I interferon secretion by plasmacytoid dendritic cells through its interleukin 10 homolog

Virology ◽

10.1016/j.virol.2009.05.013 ◽

2009 ◽

Vol 390 (2) ◽

pp. 330-337 ◽

Cited By ~ 44

Author(s):

W.L. William Chang ◽

Peter A. Barry ◽

Richard Szubin ◽

Dai Wang ◽

Nicole Baumgarth

Keyword(s):

Dendritic Cells ◽

Human Cytomegalovirus ◽

Type I Interferon ◽

Interleukin 10 ◽

Plasmacytoid Dendritic Cells ◽

Type I

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319: CD300a and CD300c on Plasmacytoid Dendritic Cells are Down-Regulated by TLR7 and TLR9 Ligand Induced Type I Interferon

Biology of Blood and Marrow Transplantation ◽

10.1016/j.bbmt.2007.12.329 ◽

2008 ◽

Vol 14 (2) ◽

pp. 118

Author(s):

D.N.J. Hart ◽

G. Clark ◽

X. Ju ◽

M. Zenke

Keyword(s):

Dendritic Cells ◽

Type I Interferon ◽

Plasmacytoid Dendritic Cells ◽

Type I ◽

Tlr9 Ligand

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Mesenchymal Stem Cells Alleviate Moderate-to-Severe Psoriasis by Reducing the Production of Type I Interferon (IFN-I) by Plasmacytoid Dendritic Cells (pDCs)

Stem Cells International ◽

10.1155/2019/6961052 ◽

2019 ◽

Vol 2019 ◽

pp. 1-13 ◽

Cited By ~ 3

Author(s):

Maosheng Chen ◽

Jing Peng ◽

Qi Xie ◽

Na Xiao ◽

Xian Su ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Dendritic Cells ◽

Type I Interferon ◽

Neutrophil Function ◽

Plasmacytoid Dendritic Cells ◽

Human Umbilical Cord ◽

Therapeutic Effects ◽

Type I ◽

Cytokines And Chemokines

The anti-inflammatory and immunomodulatory properties of mesenchymal stem cells (MSCs) have been proposed to be involved in some autoimmune diseases and have been successfully tested in patients and mice. But their contribution to psoriasis and the underlying mechanisms involved remains elusive. Here, we explored the feasibility of using human umbilical cord-derived MSC (hUC-MSC) infusion as a therapeutic approach in an imiquimod- (IMQ-) induced psoriasis mouse model. MSC infusion were found to significantly reduce the severity and development of psoriasis, inhibit the infiltration of immune cells to the skin, and downregulate the expression of several proinflammatory cytokines and chemokines. Our results provide an explanation for the therapeutic effects of MSC infusion by first suppressing neutrophil function and then downregulating the production of type I interferon (IFN-I) by plasmacytoid dendritic cells (pDCs). Therefore, we discovered a novel mechanism of stem cell therapy for psoriasis. In summary, our results showed that MSC infusion could be an effective and safe treatment for psoriasis.

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