Transforming growth factor-β 'reprograms' the differentiation of T helper 2 cells and promotes an interleukin 9–producing subset

Veldhoen, Marc; Uyttenhove, Catherine; Snick, Jacques Van; Helmby, Helena; Westendorf, Astrid M.; Buer, Jan; Martin, Bruno; Wilhelm, Christoph; Stockinger, Brigitta

doi:10.1038/ni.1659

Cited by 1,018 publications

(1,051 citation statements)

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“…The relevance of this finding for in vivo regulation of IL-9 is supported by the observations that IL-1a-and IL-1b-deficient mice have diminished IL-9 production and show increased susceptibility to T. muris [17], an infection where IL-9 stimulates worm expulsion [4]. Our results also prove for the first time that the very selective IL-9 upregulation by TGF-b/IL-4 described for naïve CD4 1 T cells activated in vitro [9] operates also during antigen restimulation of in vivo primed CD4 1 T cells, attesting the ability of this cytokine combination to transform immune T cells into selective IL-9 producers.…”

Section: Discussionsupporting

confidence: 86%

“…A recent publication, however, showed that, in the presence of IL-4 and TGF-b, naïve T cells could be programmed to selective IL-9 production [9] and failed to express T-bet, GATA3, Foxp3, or RORgt, suggesting that these cells could represent a novel Th subset, an idea confirmed in another report [10]. These results changed our perception of the IL-9 stimulating activity of TGF-b/IL-4 reported by Schmitt [11].…”

Section: Introductionmentioning

confidence: 99%

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TGF‐β interactions with IL‐1 family members trigger IL‐4‐independent IL‐9 production by mouse CD4⁺ T cells

2010

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TGF-b and IL-4 were recently shown to selectively upregulate IL-9 production by naïve CD4 1 T cells. We report here that TGF-b interactions with IL-1a, IL-1b, IL-18, and IL-33 have equivalent IL-9-stimulating activities that function even in IL-4-deficient animals. This was observed after in vitro antigenic stimulation of immunized or unprimed mice and after polyclonal T-cell activation. Based on intracellular IL-9 staining, all IL-9-producing cells were CD4 1 and 80-90% had proliferated, as indicated by reduced CFSE staining. In contrast to IL-9, IL-13 and IL-17 were strongly stimulated by IL-1 and either inhibited (IL-13) or were unaffected (IL-17) by addition of TGF-b. IL-9 and IL-17 production also differed in their dependence on IL-2 and regulation by IL-1/IL-23. As IL-9 levels were much lower in Th2 and Th17 cultures, our results identify TGF-b/IL-1 and TGF-b/IL-4 as the main control points of IL-9 synthesis.

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Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

TGF‐β interactions with IL‐1 family members trigger IL‐4‐independent IL‐9 production by mouse CD4⁺ T cells

2010

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“…16,53 While this list continues to expand, for instance with the Th9 and Th22 phenotypes, 54,55 several studies are questioning the idiosyncrasy of phenotypes. For example, there have been suggestions that Th17 cells are related to Th1 cells, 56 and that Th9 cells are a subset of Th2 cells.…”

Section: Activated Cellmentioning

confidence: 99%

Cell division curtails helper phenotype plasticity and expedites helper T‐cell differentiation

Ham

Boer

2012

Immunol Cell Biol

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Following activation by antigen, helper T cells differentiate into one of many effector phenotypes. Formulating mechanistic mathematical models combining regulatory networks at the transcriptional, translational and epigenetic level, we study how individual helper T cells may adopt their different phenotypes. For each cytokine phenotype, for example, T helper type 1 (Th1) and type 2 (Th2) cells, we find that the intracellular molecular network allows a cell to adopt one of the three states, which we interpret as naive, active and memory states. Cell division markedly speeds up the differentiation into a particular memory state because of DNA demythelation. In a memory state, cells readily resume production of the same cytokine they produced before. Using stochastic models we show that helper T-cell plasticity (that is, the ability to switch phenotype) is low during clonal expansion. Although most memory cells rapidly secrete the original cytokine upon restimulation, some adopt another phenotype and produce different cytokines, allowing for considerable diversity in the phenotypes that are adopted during a memory response. In summary, we show that helper T-cell division expedites cell differentiation by increasing DNA demethylation. We also show that plasticity is low during the clonal expansion phase, but that helper T cells may adopt alternative phenotypes during a memory response. Keywords: epigenetic regulation; helper T-cell phenotypes; mathematical modelling; transcriptional regulation For more than a century, biologists have studied the mechanisms that enable cells to encode genetic information, and how this information is passed on to the cell's progeny. 1 Besides the genetic DNA code of a cell that is replicated faithfully upon every cell division and therefore virtually identical in every cell within an individual, 2 additional 'epigenetic' information fixes differential cell development by prompting daughter cells to express a similar set of genes as their mother cell. 3 This facilitates and thus preserves the differentiation process that the mother cell and its ancestors have undergone as part of cellular diversification within an organism.A variety of biological systems have now been studied using highthroughput technologies, which provide data that allow a better understanding of information processing within a cell. [4][5][6][7] The availability of quantitative data and the apparent complexity of cellular regulatory networks have led to a data-driven mathematical modelling approach that is usually referred to as computational or systems biology. Mathematical models have revealed nonlinearity in genetic networks that allow cells to switch between states. Examples are the Lac operon 8 and cells of the haematopoietic lineage. [9][10][11][12] Recently, epigenetic regulation mediated by histone modification has been studied using similar mathematical models. [13][14][15] At the molecular level these mathematical models describe quite different genetic and epigenetic systems. Mathematically they share im...

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“…In 1995 Dr Sakaguchi60, 61 discovered another specific subpopulation of T cells, named regulatory T (Treg) cells, that were specialized for immunosuppression. More recently other subsets have been isolated named Th17 (2005),62, 63 Th9 (2008)64, 65 and Th22 (2009) 40. Finally, single‐cell RNA ‐sequencing has revealed the existence of a subpopulation of steroid‐producing cells within the Th2 compartment 23…”

Section: Introductionmentioning

confidence: 99%

Single‐cell technologies to study the immune system

Proserpio

Mahata

2015

Immunology

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SummaryThe immune system is composed of a variety of cells that act in a coordinated fashion to protect the organism against a multitude of different pathogens. The great variability of existing pathogens corresponds to a similar high heterogeneity of the immune cells. The study of individual immune cells, the fundamental unit of immunity, has recently transformed from a qualitative microscopic imaging to a nearly complete quantitative transcriptomic analysis. This shift has been driven by the rapid development of multiple single‐cell technologies. These new advances are expected to boost the detection of less frequent cell types and transient or intermediate cell states. They will highlight the individuality of each single cell and greatly expand the resolution of current available classifications and differentiation trajectories. In this review we discuss the recent advancement and application of single‐cell technologies, their limitations and future applications to study the immune system.

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Transforming growth factor-β 'reprograms' the differentiation of T helper 2 cells and promotes an interleukin 9–producing subset

Cited by 1,018 publications

References 31 publications

TGF‐β interactions with IL‐1 family members trigger IL‐4‐independent IL‐9 production by mouse CD4⁺ T cells

TGF‐β interactions with IL‐1 family members trigger IL‐4‐independent IL‐9 production by mouse CD4⁺ T cells

Cell division curtails helper phenotype plasticity and expedites helper T‐cell differentiation

Single‐cell technologies to study the immune system

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Transforming growth factor-β 'reprograms' the differentiation of T helper 2 cells and promotes an interleukin 9–producing subset

Cited by 1,018 publications

References 31 publications

TGF‐β interactions with IL‐1 family members trigger IL‐4‐independent IL‐9 production by mouse CD4+ T cells

TGF‐β interactions with IL‐1 family members trigger IL‐4‐independent IL‐9 production by mouse CD4+ T cells

Cell division curtails helper phenotype plasticity and expedites helper T‐cell differentiation

Single‐cell technologies to study the immune system

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TGF‐β interactions with IL‐1 family members trigger IL‐4‐independent IL‐9 production by mouse CD4⁺ T cells

TGF‐β interactions with IL‐1 family members trigger IL‐4‐independent IL‐9 production by mouse CD4⁺ T cells