Redefinition of the human mast cell transcriptome by deep-CAGE sequencing

Motakis, Efthymios; Guhl, Sven; Ishizu, Yuri; Itoh, Masayoshi; Kawaji, Hideya; Hoon, Michiel de; Lassmann, Timo; Carninci, Piero; Hayashizaki, Yoshihide; Zuberbier, Torsten; Forrest, Alistair R.R.; Babina, Magda

doi:10.1182/blood-2013-02-483792

Cited by 186 publications

(279 citation statements)

References 56 publications

(62 reference statements)

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“…We recently found that ex vivo and cultured skin MCs strongly differ in their transcriptomes at the whole-genome level (13). Here, we analysed the transition MCs experience on withdrawal from the skin in more detail (i) by extending several data to the protein and functional levels, (ii) by increasing the number of MC donors, (iii) by monitoring the same MC preparations over time and (iv) by investigating cultured MCs not only in the expansion phase but also upon definitive exit from the cell cycle.…”

Section: Questions Addressedmentioning

confidence: 99%

“…Mast cells were isolated from human breast skin (13)(14)(15) and cultured (in SCF + IL-4) for up to 16 weeks; at defined times, cells were analysed for proliferation (BrdU incorporation), gene expression (quantitative RT-PCR), protein expression (flow cytometry), protease activity, histamine content and stimulation by FceRI-cross-linking. All experimental procedures are detailed in the Supporting Information.…”

Section: Experimental Designmentioning

confidence: 99%

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Skin mast cells develop non‐synchronized changes in typical lineage characteristics upon culture

Guhl

Neou

Artuc

et al. 2014

Experimental Dermatology

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Despite their hematopoietic origin, mast cells (MCs) develop exclusively in tissues, hampering their ample use in research. To circumvent this problem, tissue‐derived MCs are typically first expanded in culture, but the changes MCs may undergo in the novel micromilieu are poorly defined. Here, we monitor skin MCs from a number of donors over time, revealing profound yet non‐synchronized modulations in culture. While tryptase and chymase, the most specific markers, strongly decline, FcεRI surface expression, and FcεRI‐mediated histamine release steeply increase (from ≈15.5% to ≈60%), replicated by similar increments in TNF‐α secretion. Interestingly, the modulations are independent of cell cycle progression, as they are comparable in the growth and postgrowth phase, implying they primarily result from microenvironmental conditioning. The data highlight a high degree of MC versatility, but also advise that results based on cultured MCs should be viewed with some caution, as they may not accurately reflect their counterparts in situ.

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Section: Questions Addressedmentioning

confidence: 99%

Section: Experimental Designmentioning

confidence: 99%

Skin mast cells develop non‐synchronized changes in typical lineage characteristics upon culture

Guhl

Neou

Artuc

et al. 2014

Experimental Dermatology

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“…Befitting their uniqueness, MCs have no close relative in the hematopoietic network, the best concordance found with hematopoietic progenitor cells. The overall concordance with basophils, the other major effector cell of allergic reactions, is fairly low [5], and the same applies to other myelocytes (SUPPLEMENTARY TABLE 1).…”

Section: The Fantom5 Projectmentioning

confidence: 72%

“…So, what do we really know about these cells in humans? Recent publications by functional annotation of the mammalian genome 5 (FANTOM5), a large consortium dedicated to body-wide transcriptomics and the identification of genomic regions which actually control gene activity revealed that MCs may have properties not associated with the cells before, but conversely lack functions of other immune cells commonly linked to MCs [4,5]. From an allergy point of view, these data not only offer novel insights into how the allergy machinery works at the level of MCs but they also indicate potential novel drug targets for the alleviation of allergy.…”

mentioning

confidence: 99%

Mast cell transcriptome elucidation: what are the implications for allergic disease in the clinic and where do we go next?

Babina

Motakis

Zuberbier

2014

Expert Review of Clinical Immunology

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“…Based on published microarray databases and RNA sequencing results, we identified the following potential T-cell costimulatory molecules expressed by human mast cells that can be blocked by neutralizing antibodies: OX40L (TNFSF4), ICOSL (B7H2), and LIGHT (TNFSF14) [15,16]. As shown in Figure 5, costimulation by mast cells was not inhibited using blocking antibodies against OX40L, ICOSL, or LIGHT, suggesting that the activation of CD4 + T cells by mast cells was not mediated via these receptor/ligand systems and that other, possibly unknown, receptors are responsible for T-cell costimulation by human mast cells.…”

Section: Cd4 + T-cell Proliferation Induced By MC Does Not Depend Onmentioning

confidence: 99%

Human mast cells costimulate T cells through a CD28‐independent interaction

et al. 2016

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Mast cells are innate immune cells usually residing in peripheral tissues, where they are likely to activate T-cell responses. Similar to other myeloid immune cells, mast cells can function as antigen-presenting cells. However, little is known about the capacity of human mast cells to costimulate CD4 + T cells. Here, we studied the T-cell stimulatory potential of human mast cells. Peripheral blood derived mast cells were generated and cocultured with isolated CD4 + T cells. In the presence of T-cell receptor triggering using anti-CD3, mast cells promoted strong proliferation of T cells, which was two-to fivefold stronger than the "T-cell promoting capacity" of monocytes. The interplay between mast cells and T cells was dependent on cell-cell contact, suggesting that costimulatory molecules on the mast cell surface are responsible for the effect. However, in contrast to monocytes, the T-cell costimulation by mast cells was independent of the classical costimulatory molecule CD28, or that of OX40L, ICOSL, or LIGHT. Our data show that mast cells can costimulate human CD4 + T cells to induce strong T-cell proliferation, but that therapies aiming at disrupting the interaction of CD28 and B7 molecules do not inhibit mast cell mediated T-cell activation. Additional supporting information may be found in the online version of this article at the publisher's web-site Keywords IntroductionMast cells are innate immune cells derived from myeloid progenitors. They have been originally described as one of the effector cells in allergic IgE-mediated responses. More recently, their role in immune regulation, and specifically in regulation of adaptive immune responses, has been recognized [1]. For example, we and others have shown that mast cells can function as antigenpresenting cells through cognate interactions with CD4 + T cells both in human and mouse [2][3][4]. CD4 + T-cell activation in this context was dependent on recognition of specific antigens in the Correspondence: Dr. René E. M. Toes e-mail: r.e.m.toes@lumc.nl context of MHC class II. Activation and skewing of T cells generally requires the presence of three signals, consisting of antigen presentation through MHC, costimulation, and specific cytokine signals [5]. Costimulation is the interaction of membrane-bound receptors on T cells and antigen-presenting cells that enhance signals through the T-cell receptor, and that is necessary to induce full T-cell activation, proliferation, and survival. Classical costimulation consists of CD28-mediated signaling by B7 family members on antigen-presenting cells, although different molecules, such as members of the TNF receptor superfamily or signaling lymphocyte activation molecule family are known to regulate the balance between T-cell death and survival as well [6].We have previously shown the presence of mast cells in T-cell areas of lymphoid organs [2], as well as their colocalization in synovial tissue [7], suggesting that mast cells could modulate [8,9]. This effect in the mouse was directly mediated through TNF produ...

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Redefinition of the human mast cell transcriptome by deep-CAGE sequencing

Abstract: Key Points Generated a reference transcriptome for ex vivo, cultured, and stimulated mast cells, contrasted against a broad collection of primary cells. Identified BMPs as function-modulating factors for mast cells.

Cited by 186 publications

References 56 publications

Skin mast cells develop non‐synchronized changes in typical lineage characteristics upon culture

Skin mast cells develop non‐synchronized changes in typical lineage characteristics upon culture

Mast cell transcriptome elucidation: what are the implications for allergic disease in the clinic and where do we go next?

Human mast cells costimulate T cells through a CD28‐independent interaction

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