Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors

Villani, Alexandra Chloé; Satija, Rahul; Reynolds, Gary; Sarkizova, Siranush; Shekhar, Karthik; Fletcher, James; Griesbeck, Morgane; Butler, Andrew; Zheng, Shiwei; Lazo, Suzan; Jardine, Laura; Dixon, David; Stephenson, Emily; Nilsson, Emil M.; Grundberg, Ida; McDonald, David; Filby, Andrew; Li, Weibo; Jager, Philip L. De; Rozenblatt-Rosen, Orit; Lane, Andrew A.; Haniffa, Muzlifah; Regev, Aviv; Hacohen, Nir

doi:10.1126/science.aah4573

Cited by 1,987 publications

(2,569 citation statements)

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“…(For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.) population of pre-cDCs expressing AXL that highly expresses co-stimulatory molecules (See et al, 2017;Villani et al, 2017). Although it can be deduced from these studies that bona fide pDCs still outnumber contaminating cDCs using this gating strategy, it is not known whether the extent of pre-cDC contamination varies between males and females or whether it is affected by infection.…”

Section: Discussionmentioning

confidence: 99%

TLR7 polymorphism, sex and chronic HBV infection influence plasmacytoid DC maturation by TLR7 ligands

et al. 2018

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A B S T R A C TTLR7 agonists are of high interest for the treatment of cancer, auto-immunity and chronic viral infections. They are known to activate plasmacytoid dendritic cells (pDCs) to produce high amounts of Type I Interferon (IFN) and to facilitate T and B cell responses, the latter with the help of maturation markers such as CD40, CD80 and CD86. The TLR7 single nucleotide polymorphism (SNP) rs179008 (GLn11Leu), sex and chronic viral infection have all been reported to influence pDC IFN production. It is unknown, however, whether these factors also influence pDC phenotypic maturation and thereby IFN-independent pDC functions. Furthermore, it is unclear whether SNP rs179008 influences HBV susceptibility and/or clearance.Here we investigated whether the SNP rs179008, sex and HBV infection affected phenotypic maturation of pDCs from 38 healthy individuals and 28 chronic HBV patients. In addition, we assessed SNP prevalence in a large cohort of healthy individuals (n = 231) and chronic HBV patients (n = 1054).Consistent with previous reports, the rs179008 variant allele was largely absent in Asians and more prevalent in Caucasians. Among Caucasians, the SNP was equally prevalent in healthy and chronically infected males. The SNP was, however, significantly more prevalent in healthy females than in those with chronic HBV infection (42 versus 28%), suggesting that in females it may offer protection from chronic infection. Ex vivo experiments demonstrated that induction of the co-stimulatory molecules CD40 and CD86 by TLR7 ligands, but not TLR9 ligands, was augmented in pDCs from healthy SNP-carrying females. Furthermore, CD80 and CD86 upregulation was more pronounced in females independent of the SNP. Lastly, our data suggested that chronic HBV infection impairs pDC maturation. These findings provide insight into factors determining TLR7 responses, which is important for further clinical development of TLR7-based therapies.

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Section: Discussionmentioning

confidence: 99%

TLR7 polymorphism, sex and chronic HBV infection influence plasmacytoid DC maturation by TLR7 ligands

et al. 2018

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“…3a-c). We determined the putative identity of the cells in these clusters by comparing their global gene expression patterns to those of published reference monocyte/dendritic cell (DC) clusters identified in blood samples of healthy individuals using scRNA-seq 6 (Fig. 3b,c; Supplementary Fig.…”

Section: Classification and Annotation Of Myeloid Cell Clusters Reveamentioning

confidence: 99%

The immune cell landscape in kidneys of lupus nephritis patients

Arazi

Rao

Berthier

et al. 2018

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Lupus nephritis is a potentially fatal autoimmune disease, whose current treatment is ineffective and often toxic. To gain insights into disease mechanisms, we analyzed kidney samples from lupus nephritis patients and healthy controls using single-cell RNA-seq. Our analysis revealed 21 subsets of leukocytes active in disease, including multiple populations of myeloid, T, NK and B cells, demonstrating both pro-inflammatory and resolving responses. We found evidence of local activation of B cells correlated with an age-associated B cell signature, and of progressive stages of monocyte differentiation within the kidney. A clear interferon response was observed in most cells. Two chemokine receptors, CXCR4 and CX3CR1, were broadly expressed, pointing to potential therapeutic targets. Gene expression of immune cells in urine and kidney was highly correlated, suggesting urine may be a surrogate for kidney biopsies. Our results provide a first comprehensive view of the complex network of leukocytes active in lupus nephritis kidneys.

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“…In the blood, human DC include lineage-negative (LIN-) HLA-DR+CD14-CD11c-CD123+ plasmacytoid DC and LIN-HLA-DR+CD14-CD11c+ conventional DC subsets, of which the latter can be subdivided into four different DC subsets (DC1 to DC4) based on the additional markers CLEC9A, CD141, CD1c, CD16, CD36, CD32b and CD163. 23 , 28 Blood analysis of six EOC patients and four healthy donors revealed that the HLA-DR+CD14-CD11c+ DC subset was mainly composed of CD141+CLEC9A+ DC1, CD1c+CD32b+ DC2, CD1 c+CD32b-CD36+CD163+ DC3 and CD1c-CD16+ DC4 subsets ( Suppl. Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The latter was based on a publication by Villani and co-workers 23 and consisted of the following markers: the live/dead marker yellow amine reactive dye, CD11b-AF488 (clone ICRF44), CD16-PE-CF594 (clone 3G8), CD14-PE-Cy7 (clone M5E2), HLA-DR-V500 (clone L243), CD11c-BV650 (clone B-ly6), CD163-PerCP-Cy5.5 (clone GHI/61), CD123-BV605 (clone 9F5; all from BD), CD141-APC (clone AD5–14H12, Miltenyi Biotec), CLEC9A-PE (clone 8F9), CD36-APC-Cy7 (clone 5–271; both Biolegend), CD1c-BV421 (clone L161, eBioscienes) and CD32b-AF700 (clone #190723, R&D systems).…”

Section: Methodsmentioning

confidence: 99%

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The blood mMDSC to DC ratio is a sensitive and easy to assess independent predictive factor for epithelial ovarian cancer survival

et al. 2018

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Epithelial ovarian cancer (EOC) may cause abnormal blood levels of leukocytes. This paraneoplastic manifestation is associated with a worse response to therapy and shorter survival. To understand the complexity and nature of these leukocytes, we dissected the different populations of myeloid cells and analyzed their relation to clinical outcome. Therefore, baseline blood samples of 36 EOC patients treated either with carboplatin/doxorubucin or with gemcitabine were analyzed for different subsets of monocytes/macrophages, myeloid derived suppressor cells (MDSC) and dendritic cells (DC) using multiparameter flow cytometry as well as functional assays for myeloid cell mediated suppression of antigen-specific T cell reactivity. Healthy donor blood served as control. EOC patients displayed an increase in monocytes/macrophages, monocytic MDSC (mMDSC) and CD33-CD11b+CD14-CD15- double-negative MDSC (CD33- dnMDSC) and a decrease in the frequency of DC, across all EOC subtypes. A low frequency of DC and high frequencies of monocytes/macrophages and mMDSC, but not CD33- dnMDSC, were associated with poor overall survival. Patient's monocytes/macrophages and mMDSC, but not CD33- dnMDSC, were shown to suppress T cell reactivity in vitro. The mMDSC and DC frequencies were not altered upon treatment. Importantly, the mMDSC to DC ratio was the strongest independent, highly sensitive and specific, predictive factor for survival. This was irrespective of the type of chemotherapy or disease stage and outperformed classical parameters as WHO status or time from last chemotherapy. Thus, the baseline blood mMDSC to DC ratio is a robust, independent and easy to analyze predictive factor for EOC survival, and may assist patient selection for immunotherapy.

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Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors

Cited by 1,987 publications

References 73 publications

TLR7 polymorphism, sex and chronic HBV infection influence plasmacytoid DC maturation by TLR7 ligands

TLR7 polymorphism, sex and chronic HBV infection influence plasmacytoid DC maturation by TLR7 ligands

The immune cell landscape in kidneys of lupus nephritis patients

The blood mMDSC to DC ratio is a sensitive and easy to assess independent predictive factor for epithelial ovarian cancer survival

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