Whole transcriptome-sequencing and network analysis of CD1c+ human dendritic cells identifies cytokine-secreting subsets linked to type I IFN-negative autoimmunity to the eye

Background: Inflammatory subsets of CD1c+ conventional dendritic cells (CD1c+ DCs) are promoted by type I interferons (IFN), but the molecular basis for CD1c+ DCs involvement in conditions not driven by type I IFNs is unknown. Methods: Our objective was to use RNA-sequencing of blood CD1c+ DCs and high-dimensional flow cytometry of two cohorts of autoimmune uveitis patients and healthy donors to characterize the CD1c+ DCs population of type I IFN-negative autoimmune uveitis. Results: We report that the CD1c+ DCs pool from patients with autoimmune uveitis (n=45) is skewed towards a transcriptional network characterized by surface receptor genes CX3CR1, CCR2, and CD36. We confirmed the association of the transcriptional network with autoimmune uveitis by RNA-sequencing in another case-control cohort (n=35) and demonstrated that this network was governed by NOTCH2-RUNX3 signaling. Unbiased flow cytometry analysis based on the transcriptional network identified blood CD1c+ DC subsets that can be distinguished by CX3CR1 and CD36 surface expression. A CD36+CX3CR1+CD1c+ DC subset within the novel DC3 population was diminished in peripheral blood of patients, while CD1c+ DCs expressing CD36 and CX3CR1 accumulate locally in the inflamed eye. The CD36+CX3CR1+CD1c+ DC subset showed a differential capacity to produce cytokines, including TNF-alpha, IL-6, and VEGF, but not IL-23. Conclusion: These results show that CD1c+ DC subsets defined on the basis of surface expression of CD36 and CX3CR1 are linked to type I IFN-negative human autoimmune uveitis and show a differential capacity to secrete proinflammatory mediators that drive its pathophysiology.

Download Full-text

Decision letter for "NCoR1 fine‐tunes type‐I IFN response in cDC1 dendritic cells by directly regulating Myd88‐IRF7 axis under TLR9"

10.1002/eji.202048566/v2/decision1 ◽

2020 ◽

Keyword(s):

Dendritic Cells ◽

Type I ◽

Type I Ifn

Download Full-text

Review for "NCoR1 fine‐tunes type‐I IFN response in cDC1 dendritic cells by directly regulating Myd88‐IRF7 axis under TLR9"

10.1002/eji.202048566/v1/review2 ◽

2020 ◽

Keyword(s):

Dendritic Cells ◽

Type I ◽

Type I Ifn

Download Full-text

PLASMACYTOID DENDRITIC CELLS FUNCTION IN HIV INFECTION

Clinical & Investigative Medicine ◽

10.25011/cim.v31i4.4808 ◽

2008 ◽

Vol 31 (4) ◽

pp. 13

Author(s):

Martin Hyrcza ◽

Mario Ostrowski ◽

Sandy Der

Keyword(s):

Dendritic Cells ◽

Influenza Virus ◽

Hiv Infection ◽

Gene Transcription ◽

Sendai Virus ◽

Plasmacytoid Dendritic Cells ◽

Type I Interferons ◽

Interferon Response ◽

Type I ◽

Type I Ifn

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.

Download Full-text

Faculty Opinions recommendation of A minor population of splenic dendritic cells expressing CD19 mediates IDO-dependent T cell suppression via type I IFN signaling following B7 ligation.

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

10.3410/f.1026476.325190 ◽

2005 ◽

Author(s):

Richard Williams

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Type I ◽

Type I Ifn ◽

T Cell Suppression ◽

Minor Population ◽

Cell Suppression ◽

A Minor

Download Full-text

STING-Licensed Macrophages Prime Type I IFN Production by Plasmacytoid Dendritic Cells in the Bone Marrow during Severe Plasmodium yoelii Malaria

PLoS Pathogens ◽

10.1371/journal.ppat.1005975 ◽

2016 ◽

Vol 12 (10) ◽

pp. e1005975 ◽

Cited By ~ 39

Author(s):

Emily Spaulding ◽

David Fooksman ◽

Jamie M. Moore ◽

Alex Saidi ◽

Catherine M. Feintuch ◽

...

Keyword(s):

Bone Marrow ◽

Dendritic Cells ◽

Plasmodium Yoelii ◽

Plasmacytoid Dendritic Cells ◽

Type I ◽

Type I Ifn ◽

Prime Type

Download Full-text

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.

Download Full-text

Dysregulated miRNome of plasmacytoid dendritic cells from patients with Sjögren’s syndrome is associated with processes at the centre of their function

Rheumatology ◽

10.1093/rheumatology/kez195 ◽

2019 ◽

Vol 58 (12) ◽

pp. 2305-2314 ◽

Cited By ~ 5

Author(s):

Maarten R Hillen ◽

Eleni Chouri ◽

Maojie Wang ◽

Sofie L M Blokland ◽

Sarita A Y Hartgring ◽

...

Keyword(s):

Cell Death ◽

Dendritic Cells ◽

Mammalian Target Of Rapamycin ◽

Plasmacytoid Dendritic Cells ◽

Type I ◽

Large Set ◽

Type I Ifn ◽

Stable Isotope Labelling ◽

Proteomic Approach ◽

Novel Targets

Abstract Objective A considerable body of evidence supports a role for type-I IFN in the pathogenesis of primary SS (pSS). As plasmacytoid dendritic cells (pDCs) are a major source of type-I IFN, we investigated their molecular regulation by measuring expression of a large set of miRNAs. Methods pDCs were isolated from peripheral blood of pSS patients (n = 30) and healthy controls (n = 16) divided into two independent cohorts (discovery and replication). Screening of 758 miRNAs was assessed by an OpenArray quantitative PCR-based technique; replication of a set of identified miRNAs was performed by custom array. Functional annotation of miRNA targets was performed using pathway enrichment. Novel targets of miR-29a and miR-29c were identified using a proteomic approach (stable isotope labelling with amino acids in cell culture). Results In the discovery cohort, 20 miRNAs were differentially expressed in pSS pDCs compared with healthy control pDCs. Of these, differential expression of 10 miRNAs was confirmed in the replication cohort. The dysregulated miRNAs were involved in phosphoinositide 3-kinase-Ak strain transforming and mammalian target of rapamycin signalling, as well as regulation of cell death. In addition, a set of novel protein targets of miR-29a and miR-29c were identified, including five targets that were regulated by both miRs. Conclusion The dysregulated miRNome in pDCs of patients with pSS is associated with aberrant regulation of processes at the centre of pDC function, including type-I IFN production and cell death. As miR-29a and miR-29c are pro-apoptotic factors and several of the novel targets identified here are regulators of apoptosis, their downregulation in patients with pSS is associated with enhanced pDC survival.

Download Full-text