Sources of Type I Interferons in Infectious Immunity: Plasmacytoid Dendritic Cells Not Always in the Driver's Seat

Ali, Shafaqat; Mann-Nüttel, Ritu; Schulze, Anja; Richter, Lisa; Alferink, Judith; Scheu, Stefanie

doi:10.3389/fimmu.2019.00778

Cited by 123 publications

(113 citation statements)

References 199 publications

(265 reference statements)

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“…69 Our studies and others similarly suggest that pathological type I IFN production in SLE is not limited to pDCs. 69 Our studies and others similarly suggest that pathological type I IFN production in SLE is not limited to pDCs.…”

Section: Pathogenic Effects Of Pdcssupporting

confidence: 66%

“…pDCs are often considered the principal source of type I IFNs in vivo; however, it is becoming clear that production of type I IFN, especially the rapidly induced high-affinity IFNβ, is accomplished a variety of cell types and cannot be mainly attributed to pDCs. 69 Our studies and others similarly suggest that pathological type I IFN production in SLE is not limited to pDCs. 1,67,[70][71][72] pDCs have long been prime suspects owing to a large body of literature confirming their high capacity for type I IFN production following viral infection or stimulation with viral nucleic acid mimics.…”

Section: Pathogenic Effects Of Pdcssupporting

confidence: 66%

“…74 The cellular sources of type I IFN production depend on many factors, including the nature and multiplicity of the stimulus, temporal factors, as well as genetic factors. 69,71 In human studies, pDCs clearly have a significant presence in cutaneous lupus 75 F I G U R E 2 Lupus susceptible B-cells exhibit a higher potency to become GC B cells within the same environment. BM-chimeric mice were generated by reconstitution of CD45.2 Rag1 -⁄mice with equal numbers of BM derived from CD45.2 B6-Ifnb -⁄mice, CD45.1 Ifnb +/+ (WT) B6 mice and GFP + BXD2 mice.…”

Section: Pathogenic Effects Of Pdcsmentioning

confidence: 99%

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Autoreactive B cells in SLE, villains or innocent bystanders?

Hamilton

Hsu

Mountz

2019

Immunological Reviews

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Autoreactive B-cell development in SLE (systemic lupus erythematosus) is often considered in terms of the extrinsic stimuli and factors that drive B cells into autoantibody production. This review focuses on the novel concept that autoreactive B cells are initially programmed at the transitional stage for heightened susceptibility for development into autoantibody secreting plasmablasts (Figure 1). During peripheral B-cell development in the spleen, transitional B-cells expressing elevated levels of endogenous intracellular interferon-β (IFNβ) exhibit enhanced survival and activation through the B-cell receptor (BCR), a feature associated with more active SLE, particularly in African American (AA) patients. 1 Following passage through the transitional stage, a second major defect is the failure of B cells to maintain the integrity of tolerogenic splenic marginal zone macrophages (MZM), which normally function to remove apoptotic cell debris in a non-inflammatory fashion through upregulation of indoleamine-pyrrole 2,3-dioxygenase (IDO). 2 This failure is amplified by the type I IFN-driven migratory properties of marginal zone-precursor (MZ-P) B cells as they lose their tethering to sphingosine-1-phosphate (S1P) and drift across the follicular exclusion barrier. 3-8 Here they act as potent antigen-carrying, co-stimulatory cells expressing inflammatory cytokine IL-6 and low levels of the antiinflammatory cytokine IL-10. 9 In addition, Ag transporting MZ-P B-cells Abstract The current concepts for development of autoreactive B cells in SLE (systemic lupus erythematosus) focus on extrinsic stimuli and factors that provoke B cells into tolerance loss. Traditionally, major tolerance loss pathways are thought to be regulated by factors outside the B cell including autoantigen engagement of the B-cell receptor (BCR) with simultaneous type I interferon (IFN) produced by dendritic cells, especially plasmacytoid dendritic cells (pDCs). Later, in autoreactive follicles, B-cells encounter T-follicular helper cells (Tfh) that produce interleukin (IL)-21, IL-4 and pathogenic cytokines, IL-17 and IFN gamma (IFNɣ). This review discusses these mechanisms and also highlights recent advances pointing to the peripheral transitional B-cell stage as a major juncture where transient autocrine IFNβ expression by developing B-cells imprints a heightened susceptibility to external factors favoring differentiation into autoantibody-producing plasmablasts. Recent studies highlight transitional B-cell heterogeneity as a determinant of intrinsic resistance or susceptibility to tolerance loss through the shaping of B-cell responsiveness to cytokines and other environment factors.

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Section: Pathogenic Effects Of Pdcssupporting

confidence: 66%

Section: Pathogenic Effects Of Pdcssupporting

confidence: 66%

Section: Pathogenic Effects Of Pdcsmentioning

confidence: 99%

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Autoreactive B cells in SLE, villains or innocent bystanders?

Hamilton

Hsu

Mountz

2019

Immunological Reviews

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“…However, none of the bovine studies conclusively demonstrated the main source of IFNs was pDC. Recent findings in mouse models indicate that pDC may have been overestimated in regard to their importance for early IFN type I production and highlight other sources [97]. Additionally, when human pDC were stimulated on a single‐cell basis, only a small fraction was capable of IFN‐α production (<0.02% IFN‐α‐producing pDCs) [98].…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic profiling of bovine blood dendritic cells and monocytes following TLR stimulation

et al. 2020

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Dendritic cells (DC) and monocytes are vital for the initiation of innate and adaptive immune responses. Recently, we identified bona fide DC subsets in blood of cattle, revealing subset‐ and species‐specific transcription of toll‐like receptors (TLR). In the present study, we analyzed phenotypic and transcriptional responses of bovine DC subsets and monocytes to in vitro stimulation with four to six different TLR ligands. Bovine DC subsets, especially plasmacytoid DC (pDC), showed a clear increase of CCR7, CD25, CD40, CD80, CD86, and MHC‐II expression both on mRNA and protein level. Flow cytometric detection of p38 MAPK phosphorylation 15 min after stimulation confirmed activation of DC subsets and monocytes in accordance with TLR gene expression. Whole‐transcriptome sequencing of sorted and TLR‐stimulated subsets revealed potential ligand‐ and subset‐specific regulation of genes associated with inflammation, T‐cell co‐stimulation, migration, metabolic reprogramming, and antiviral activity. Gardiquimod was found to evoke strong responses both in DC subsets and monocytes, while Poly(I:C) and CpG preferentially triggered responses in cDC1 and pDC, respectively. This in‐depth analysis of ligand responsiveness is essential for the rational design of vaccine adjuvants in cattle, and provides a solid basis for comparative studies on DC and monocyte biology across species.

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“…Under homeostatic conditions, most cells produce moderate amounts of type I IFN, but specialized cells of the immune system, mainly plasmacytoid dendritic cells (pDCs), produce high amounts when activated [123][124][125]. All type I IFNs signal through a ubiquitously expressed receptor composed of the IFNAR1 and the IFNAR2 chain (Table 1).…”

Section: Type I Ifnsmentioning

confidence: 99%

TYK2 in Tumor Immunosurveillance

Karjalainen¹,

Shoebridge²,

Krunic³

et al. 2020

Cancers

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We review the history of the tyrosine kinase 2 (TYK2) as the founding member of the Janus kinase (JAK) family and outline its structure-function relation. Gene-targeted mice and hereditary defects of TYK2 in men have established the biological and pathological functions of TYK2 in innate and adaptive immune responses to infection and cancer and in (auto-)inflammation. We describe the architecture of the main cytokine receptor families associated with TYK2, which activate signal transducers and activators of transcription (STATs). We summarize the cytokine receptor activities with well characterized dependency on TYK2, the types of cells that respond to cytokines and TYK2 signaling-induced cytokine production. TYK2 may drive beneficial or detrimental activities, which we explain based on the concepts of tumor immunoediting and the cancer-immunity cycle in the tumor microenvironment. Finally, we summarize current knowledge of TYK2 functions in mouse models of tumor surveillance. The biology and biochemistry of JAKs, TYK2-dependent cytokines and cytokine signaling in tumor surveillance are well covered in recent reviews and the oncogenic properties of TYK2 are reviewed in the recent Special Issue ‘Targeting STAT3 and STAT5 in Cancer’ of Cancers.

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Sources of Type I Interferons in Infectious Immunity: Plasmacytoid Dendritic Cells Not Always in the Driver's Seat

Cited by 123 publications

References 199 publications

Autoreactive B cells in SLE, villains or innocent bystanders?

Autoreactive B cells in SLE, villains or innocent bystanders?

Transcriptomic profiling of bovine blood dendritic cells and monocytes following TLR stimulation

TYK2 in Tumor Immunosurveillance

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