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Distinct progenitor lineages contribute to the heterogeneity of plasmacytoid dendritic cells.

ABSTRACT: Plasmacytoid dendritic cells (pDCs) are an immune subset devoted to the production of high amounts of type 1 interferons in response to viral infections. Whereas conventional dendritic cells (cDCs) originate mostly from a common dendritic cell progenitor (CDP), pDCs have been shown to develop from both CDPs and common lymphoid progenitors. Here, we found that pDCs developed predominantly from IL-7R⁺ lymphoid progenitor cells. Expression of SiglecH and Ly6D defined pDC lineage commitment along the lymphoid branch. Transcriptional characterization of SiglecH⁺Ly6D⁺ precursors indicated that pDC development requires high expression of the transcription factor IRF8, whereas pDC identity relies on TCF4. RNA sequencing of IL-7R⁺ lymphoid and CDP-derived pDCs mirrored the heterogeneity of mature pDCs observed in single-cell analysis. Both mature pDC subsets are able to secrete type 1 interferons, but only myeloid-derived pDCs share with cDCs their ability to process and present antigen.

SUBMITTER: Rodrigues PF

PROVIDER: S-EPMC7614340 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Distinct progenitor lineages contribute to the heterogeneity of plasmacytoid dendritic cells.

Rodrigues Patrick Fernandes PF Alberti-Servera Llucia L Eremin Anna A Grajales-Reyes Gary E GE Ivanek Robert R Tussiwand Roxane R

Nature immunology 20180620 7

Plasmacytoid dendritic cells (pDCs) are an immune subset devoted to the production of high amounts of type 1 interferons in response to viral infections. Whereas conventional dendritic cells (cDCs) originate mostly from a common dendritic cell progenitor (CDP), pDCs have been shown to develop from both CDPs and common lymphoid progenitors. Here, we found that pDCs developed predominantly from IL-7R<sup>+</sup> lymphoid progenitor cells. Expression of SiglecH and Ly6D defined pDC lineage commitme ...[more]

PMID: 29925996

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Project description:UnlabelledPlasmacytoid dendritic cells (pDCs) are key components of the innate immune response that are capable of synthesizing and rapidly releasing vast amounts of type I interferons (IFNs), particularly IFN-α. Here we investigated whether pDCs, often regarded as a mere source of IFN, discriminate between various functionally discrete stimuli and to what extent this reflects differences in pDC responses other than IFN-α release. To examine the ability of pDCs to differentially respond to various doses of intact and infectious HIV, hepatitis C virus, and H1N1 influenza virus, whole-genome gene expression analysis, enzyme-linked immunosorbent assays, and flow cytometry were used to investigate pDC responses at the transcriptional, protein, and cellular levels. Our data demonstrate that pDCs respond differentially to various viral stimuli with significant changes in gene expression, including those involved in pDC activation, migration, viral endocytosis, survival, or apoptosis. In some cases, the expression of these genes was induced even at levels comparable to that of IFN-α. Interestingly, we also found that depending on the viral entity and the viral titer used for stimulation, induction of IFN-α gene expression and the actual release of IFN-α are not necessarily temporally coordinated. In addition, our data suggest that high-titer influenza A (H1N1) virus infection can stimulate rapid pDC apoptosis.ImportancePlasmacytoid dendritic cells (pDCs) are key players in the viral immune response. With the host response to viral infection being dependent on specific virus characteristics, a thorough examination and comparison of pDC responses to various viruses at various titers is beneficial for the field of virology. Our study illustrates that pDC infection with influenza virus, HIV, or hepatitis C virus results in a unique and differential response to each virus. These results have implications for future virology research, vaccine development, and virology as a whole.

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Distinct progenitor lineages contribute to the heterogeneity of plasmacytoid dendritic cells.

Publications

Distinct progenitor lineages contribute to the heterogeneity of plasmacytoid dendritic cells.

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