A HaemAtlas: characterizing gene expression in differentiated human blood cells

Watkins, Nicholas A.; Gusnanto, Arief; Bono, Bernard de; De, Subhajyoti; Miranda‐Saavedra, Diego; Hardie, Debbie L.; Angenent, W.; Attwood, Antony; Ellis, Peter; Erber, Wendy N.; Foad, Nicola; Garner, Stephen F.; Isacke, Clare M.; Jolley, Jennifer; Koch, Kerstin; Macaulay, Iain C.; Morley, Sarah L.; Rendon, Augusto; Rice, Kate; Taylor, Niall; Thijssen-Timmer, Daphne C.; Tijssen, Marloes R.; Schoot, C. Ellen van der; Wernisch, Lorenz; Winzer, Thilo; Dudbridge, Frank; Buckley, Christopher D.; Langford, Cordelia; Teichmann, Sarah A.; Göttgens, Berthold; Ouwehand, Willem H.

doi:10.1182/blood-2008-06-162958

Cited by 224 publications

(285 citation statements)

References 43 publications

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“…In addition, comparison of gene expression in human leukocytes identified DKK3 as one of the five genes uniquely expressed in CD8 T cells (26). In light of our finding, we suggest that DKK3 expression may be restricted only to subsets of tolerant CD8 T cells.…”

Section: Discussionmentioning

confidence: 74%

Dickkopf-3, an immune modulator in peripheral CD8 T-cell tolerance

Papatriantafyllou

Moldenhauer²,

Ludwig

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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In healthy individuals, T cells react against incoming pathogens, but remain tolerant to self-antigens, thereby preventing autoimmune reactions. CD4 regulatory T cells are major contributors in induction and maintenance of peripheral tolerance, but a regulatory role has been also reported for several subsets of CD8 T cells. To determine the molecular basis of peripheral CD8 T-cell tolerance, we exploited a double transgenic mouse model in which CD8 T cells are neonatally tolerized following interaction with a parenchymal self-antigen. These tolerant CD8 T cells have regulatory capacity and can suppress T cells in an antigen-specific manner during adulthood. Dickkopf-3 (DKK3) was found to be expressed in the tolerant CD8 T cells and to be essential for the observed CD8 T-cell tolerance. In vitro, genetic deletion of DKK3 or blocking with antibodies restored CD8 T-cell proliferation and IL-2 production in response to the tolerizing self-antigen. Moreover, exogenous DKK3 reduced CD8 T-cell reactivity. In vivo, abrogation of DKK3 function reversed tolerance, leading to eradication of tumors expressing the target antigen and to rejection of autologous skin grafts. Thus, our findings define DKK3 as a immune modulator with a crucial role for CD8 T-cell tolerance.immune tolerance | parenchymal cells | autoimmunity

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Section: Discussionmentioning

confidence: 74%

Dickkopf-3, an immune modulator in peripheral CD8 T-cell tolerance

Papatriantafyllou

Moldenhauer²,

Ludwig

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…A recent megakaryocyte (MK) transcriptome study (16) reported that Fzd4 and 6 were the most abundantly expressed Fzd isoforms in MKs, suggesting that these may also present in platelets. Indeed, we detected Fzd4 and 6 transcripts (Fig.…”

Section: Fzd6 Is Present and Functional In Plateletsmentioning

confidence: 99%

Canonical Wnt signaling negatively regulates platelet function

Steele

Harper

Macaulay

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Wnts regulate important intracellular signaling events, and dysregulation of the Wnt pathway has been linked to human disease. Here, we uncover numerous Wnt canonical effectors in human platelets where Wnts, their receptors, and downstream signaling components have not been previously described. We demonstrate that the Wnt3a ligand inhibits platelet adhesion, activation, dense granule secretion, and aggregation. Wnt3a also altered platelet shape change and inhibited the activation of the small GTPase RhoA. In addition, we found the Wnt-␤-catenin signaling pathway to be functional in platelets. Finally, disruption of the Wnt Frizzled 6 receptor in the mouse resulted in a hyperactivatory platelet phenotype and a reduced sensitivity to Wnt3a. Taken together our studies reveal a novel functional role for Wnt signaling in regulating anucleate platelet function and may provide a tractable target for future antiplatelet therapy.Wnt-␤-catenin pathway ͉ integrin ␣IIb␤3 ͉ frizzled 6 knockout mice A nucleate platelets are the principle effectors of haemostasis and are found circulating in a nonadhesive, quiescent state. At sites of vascular damage, platelets adhere to various exposed subendothelial matrix proteins and are activated, converting from a resting, discoid shape into larger, flattened structures with extended pseudopodia (1). Such activated platelets secrete and synthesize further agonists, inflammatory mediators, and vasoactive substances and through conformational changes in their major integrin receptor, ␣IIb␤3, aggregate to other platelets via fibrinogen (Fb) to form a haemostatic plug (2). Aberrant platelet activation can cause pathological thrombus formation, leading to thrombosis and ultimately vessel occlusion and tissue ischemia, the processes underlying myocardial infarction and stroke. Understanding the regulation of platelet activity is thus fundamental to comprehending thrombotic disorders and developing therapeutic strategies.The mammalian Wnt gene family is comprised of 19 secreted Wnt glycoproteins, which play essential roles in cell proliferation, cell-fate determination, and cell-fate differentiation during embryonic development and adult homeostasis (3, 4). These Wnt ligands activate a number of different signaling pathways via distinct receptors and downstream effectors to mediate effects on gene transcription and cell adhesion/migration (5, 6). For the Wnt-␤-catenin (␤-cat) signaling pathway (Fig. 1A), traditionally referred to as the ''canonical'' pathway, Wnts bind to a surface receptor complex comprised of a Frizzled (Fzd) receptor and the Lipoprotein Receptor-related Protein 5/6 (LRP5/6) coreceptor (5, 7). The signal is then transduced to the cytoplasmic protein Dishevelled (Dvl) where downstream pathways regulate the stability of ␤-cat (5, 7). In the absence of Wnt, ␤-cat is phosphorylated by a destruction complex containing Casein Kinase 1 (CK1), Glycogen Synthase Kinase 3␤ (GSK3␤), Axin-1, FRAT-1, and Adenomatous Polyposis Coli (APC), which targets ␤-cat for degradation via ubiquitina...

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“…Here we performed a conservation analysis of the most differentially expressed genes in resting T, B, NK, and myeloid cells in the mouse and human at the genome-wide level (see Methods) (Chambers et al 2007;Watkins et al 2009). Our analysis revealed that among trans-membrane (TM) or secreted protein coding genes, those specifically expressed in NK cells have proportionally fewer orthologs across all vertebrates compared with other immune cells.…”

Section: Conservation Analysis Of Mammalian T- B- Nk- and Myeloidcmentioning

confidence: 99%

“…In mouse and human, many antibodies for these markers are available and can be used to isolate homogeneous immune cell populations using flow cytometry. Gene expression profiling studies of isolated immune cell populations have further allowed genome-wide identification of cell-type-specific genes (Chambers et al 2007;Watkins et al 2009;Shay and Kang 2013;Vu Manh et al 2014). These studies revealed an overall conservation of immune cells' gene expression between mouse and human ).…”

mentioning

confidence: 99%

Single-cell transcriptome analysis of fish immune cells provides insight into the evolution of vertebrate immune cell types

et al. 2017

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The immune system of vertebrate species consists of many different cell types that have distinct functional roles and are subject to different evolutionary pressures. Here, we first analyzed conservation of genes specific for all major immune cell types in human and mouse. Our results revealed higher gene turnover and faster evolution of trans-membrane proteins in NK cells compared with other immune cell types, and especially T cells, but similar conservation of nuclear and cytoplasmic protein coding genes. To validate these findings in a distant vertebrate species, we used single-cell RNA sequencing of lck:GFP cells in zebrafish and obtained the first transcriptome of specific immune cell types in a nonmammalian species. Unsupervised clustering and single-cell TCR locus reconstruction identified three cell populations, T cells, a novel type of NK-like cells, and a smaller population of myeloid-like cells. Differential expression analysis uncovered new immunecell-specific genes, including novel immunoglobulin-like receptors, and neofunctionalization of recently duplicated paralogs. Evolutionary analyses confirmed the higher gene turnover of trans-membrane proteins in NK cells compared with T cells in fish species, suggesting that this is a general property of immune cell types across all vertebrates.

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A HaemAtlas: characterizing gene expression in differentiated human blood cells

Cited by 224 publications

References 43 publications

Dickkopf-3, an immune modulator in peripheral CD8 T-cell tolerance

Dickkopf-3, an immune modulator in peripheral CD8 T-cell tolerance

Canonical Wnt signaling negatively regulates platelet function

Single-cell transcriptome analysis of fish immune cells provides insight into the evolution of vertebrate immune cell types

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