Sequential Polarization and Imprinting of Type 1 T Helper Lymphocytes by Interferon-γ and Interleukin-12

Schulz, Edda G.; Mariani, Luca; Radbruch, Andreas; Höfer, Thomas

doi:10.1016/j.immuni.2009.03.013

Cited by 236 publications

(220 citation statements)

References 40 publications

Supporting

Mentioning

211

Contrasting

Unclassified

Order By: Relevance

“…Interestingly, IFN-g-induced activation of STAT1 was not sufficient to induce significant expression of Ifng (Fig. 3A), unlike shown previously in naïve Th cells [20,24]. Stimulation with IFN-g did not change the expression level of RORgt but resulted in a detectable increase of T-bet expression as assessed by intracellular immunofluorescence (Fig.…”

mentioning

confidence: 47%

“…In vitro-generated Th17 cells responded to IL-12, by phosphorylation of STAT4 in all cells (Fig. 1C), and expression of IFN-g by more than 40% of the cells ([17] and data not shown).To confirm that downregulation of IL-12Rb2 chain expression is not a transient consequence of TCR activation [20,21], we directly isolated splenic Th cells based on the surface expression of IL-12Rb2 ( Fig. 2A, gating for viable CD4 1 Th cells shown in Supporting Information Fig.…”

mentioning

confidence: 73%

See 1 more Smart Citation

IFN‐γ and IL‐12 synergize to convert in vivo generated Th17 into Th1/Th17 cells

et al. 2010

Self Cite

View full text Add to dashboard Cite

Th1 and Th17 cells are distinct lineages of effector/memory cells, imprinted for reexpression of , by upregulated expression of T-bet and retinoic acid-related orphan receptor ct (RORct) , respectively. Apparently, Th1 and Th17 cells share tasks in the control of inflammatory immune responses. Th cells coexpressing IFN-c and IL-17 have been observed in vivo, but it remained elusive, how these cells had been generated and whether they represent a distinct lineage of Th differentiation. It has been shown that ex vivo isolated Th1 and Th17 cells are not interconvertable by TGF-b/IL-6 and IL-12, respectively. Here, we show that ex vivo isolated Th17 cells can be converted into Th1/Th17 cells by combined IFN-c and IL-12 signaling. IFN-c is required to upregulate expression of the IL-12Rb2 chain, and IL-12 for Th1 polarization. These Th1/Th17 cells stably coexpress RORct and T-bet at the single-cell level. Our results suggest a molecular pathway for the generation of Th1/Th17 cells in vivo, which combine the pro-inflammatory potential of Th1 and Th17 cells. IntroductionTh1 cells, with a memory for IFN-g expression and determined by the master transcription factor T-bet, are considered to be essential for protection against intracellular pathogens, and had been viewed as the major pathogenic drivers of chronic autoimmune inflammation, e.g. EAE [1][2][3], uveitis [4] or colitis [5]. Recently, Th17 cells, with a memory for expression of IL-17 and determined by the transcription factor retinoic acid related orphan receptor gt (RORgt), have been identified as another pathogenic Th-cell lineage driving pathogenesis in these autoimmune models [6,7]. Th17 cells contribute to inflammation through the recruitment of neutrophils and the induction of secretion of pro-inflammatory mediators such as IL-6, IL-8, TNF-a, IL-1b, CXCL1, CXCL10 and matrix metalloproteinases from tissue cells (reviewed in [8]). Th1 cells contribute to inflammation by activation of macrophages [9]. The concerted action of IFN-g and IL-17 has been shown to be essential in the effective induction and maintenance of autoimmunity [10,11], e.g. Th1 cells being required for the recruitment of Th17 cells into the central nervous system in EAE.In inflamed tissue of autoimmune patients, Th cells coexpressing IFN-g and IL-17 have been identified [12][13][14].Ã These authors have contributed equally to this study. ResultsIn vivo, Th17 cells do not express IL-12Rb2 and do not respond to IL-12Although IL-17-expressing cells isolated from cultures stimulated in vitro respond to subsequent stimulation with IL-12 with gain of IFN-g expression and loss of IL-17 expression (Fig. 1A, upper panel), IL-17 expressing cells directly isolated ex vivo maintained IL-17 expression and could not be induced to express IFN-g in the presence of IL-12 (Fig. 1A, lower panel) [17,19]. To identify the molecular mechanism of refraction of in vivo generated Th17 cells to conversion by IL-12, we here compared the expression of genes relevant for IL-12 signaling by Th17 cells generated in vit...

show abstract

mentioning

confidence: 47%

mentioning

confidence: 73%

IFN‐γ and IL‐12 synergize to convert in vivo generated Th17 into Th1/Th17 cells

et al. 2010

Self Cite

View full text Add to dashboard Cite

show abstract

“…Ever since the original classification of circulating memory CD4 T cells into Th1 and Th2 cells,82 functional compartmentalization of antigen‐experienced T cells has become a favorite exercise of immunologists 83, 84, 85. We have shown that GATA3 mediates the epigenetic imprinting of the interleukin‐4 ( Il4 ) gene,86, 87 and how imprinting of the interferon‐γ ( Ifng ) gene is induced by STAT4 88, 89. Most importantly, we and others have shown that imprinting of cytokine genes in activated naive T cells but not in memory T cells requires progression through the S phase of the first cell division.…”

Section: Circulating Memory T Lymphocytesmentioning

confidence: 99%

Immunological memories of the bone marrow

Chang

Tokoyoda

Radbruch

2018

Immunological Reviews

Self Cite

View full text Add to dashboard Cite

SummaryMemory for antigens once encountered is a hallmark of the immune system of vertebrates, providing us with an immunity adapted to pathogens of our environment. Despite its fundamental relevance, the cells and genes representing immunological memory are still poorly understood. Here we discuss the concept of a circulating, proliferating, and ubiquitous population of effector lymphocytes vs concepts of resting and dormant populations of dedicated memory lymphocytes, distinct from effector lymphocytes and residing in defined tissues, particularly in barrier tissues and in the bone marrow. The lifestyle of memory plasma cells of the bone marrow may serve as a paradigm, showing that persistence of memory lymphocytes is not defined by intrinsic “half‐lives”, but rather conditional on distinct survival signals provided by dedicated niches. These niches are organized by individual mesenchymal stromal cells. They define the capacity of immunological memory and regulate its homeostasis.

show abstract

“…22,23 Here, we extend an established model for master transcription factors with epigenetic processes to investigate the differentiation, memory formation and plasticity of helper T cells. Helper T-cell differentiation has been studied extensively using mathematical models, 9,10,[24][25][26][27][28][29][30][31] but to the best of our knowledge, this is the first attempt to combine genetic and epigenetic levels of regulation in mechanistic models for cellular differentiation. Using analytical and numerical approaches, we show that cell division during clonal expansion markedly increases the speed of differentiation into functional helper T cells.…”

mentioning

confidence: 99%

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

Ham

Boer

2012

Immunol Cell Biol

View full text Add to dashboard Cite

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...

show abstract

Sequential Polarization and Imprinting of Type 1 T Helper Lymphocytes by Interferon-γ and Interleukin-12

Cited by 236 publications

References 40 publications

IFN‐γ and IL‐12 synergize to convert in vivo generated Th17 into Th1/Th17 cells

IFN‐γ and IL‐12 synergize to convert in vivo generated Th17 into Th1/Th17 cells

Immunological memories of the bone marrow

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

Contact Info

Product

Resources

About