Autoregulation of Th1-mediated inflammation by <i>twist1 </i>

Niesner, Uwe; Albrecht, Inka; Janke, Marko; Doebis, Cornelia; Loddenkemper, Christoph; Lexberg, Maria H.; Eulenburg, Katharina; Kreher, Stephan; Koeck, Juliana; Baumgrass, Ria; Bonhagen, Kerstin; Kamradt, Thomas; Enghard, Philipp; Humrich, Jens Y; Rutz, Sascha; Schulze-Topphoff, Ulf; Aktaş, Orhan; Bartfeld, Sina; Radbruch, Helena; Hegazy, Ahmed N.; Löhning, Max; Baumgart, Daniel C.; Duchmann, Rainer; Rudwaleit, Martín; Häupl, Thomas; Gitelman, Inna; Krenn, Veit; Gruen, J.; Sieper, J.; Zeitz, Martin; Wiedenmann, Bertram; Zipp, Frauke; Hamann, Alf; Janitz, Michael; Scheffold, Alexander; Burmester, Gerd R; Chang, Hyun Dong; Radbruch, Andreas

doi:10.1084/jem.20072468

Cited by 99 publications

(141 citation statements)

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“…Cell culture and apoptosis induction Naïve CD4 1 CD62L 1 lymphocytes from 6 to 8-wk-old DO11.10 or OT2 mice were isolated and polarized under Th1 or Th2 conditions as described elsewhere [29]. Irradiated (30Gy) congenic BALB/c or C57BL/6 splenocytes were used as APC at a ratio of 5:1 and the cognate peptide ova 323-339 (R. VolkmerEngert, Humboldt University of Berlin, Germany) was added at 0.5 mM.…”

Section: Flow Cytometrymentioning

confidence: 99%

“…The shRNA expression vector was generated as described previously [29]. The Hopx target sequence was designed with Dharmacon siRNA Design tool (5 0 -GCAGATCTGTTACGGA-CTA-3 0 ).…”

Section: Retroviral Expression Vectors and Retroviral Infectionmentioning

confidence: 99%

“…Functional differentiation into Th1 cells was achieved by adding IL-12. Cells were restimulated every 6 days for up to four cycles, and gene expression profiles of cells stimulated once or four times were compared as described previously [29]. Hopx was expressed in Th1 cells, and its expression was up-regulated in Th1 cells that had been repeatedly restimulated (Supporting Information Fig.…”

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confidence: 99%

“…We have shown before that, to this end, repeatedly restimulated Th1 cells express distinct genes of high functional relevance, genes not expressed by Th2, Th17 or regulatory T cells. One such gene is twist1, a gene limiting the inflammatory potential of repeatedly restimulated Th1 cells [29]. Expression of twist1 is induced by concomitant signaling of the TCR and Stat4, is transient upon TCR signaling, and incrementally increases upon repeated restimulation.…”

mentioning

confidence: 99%

“…In total, 14 days later, mice were sacrificed and knee joints were fixed in 10% formaldehyde, decalcified in saturated EDTA solution and embedded in paraffin. Knee joint sections were stained with hematoxylin/eosin and scored for exudates, granulocyte infiltration, hyperplasia, fibroblast proliferation/mononuclear cell infiltration, periarticular mononuclear cell infiltration (each scoring 0-3), bone/cartilage destruction (scoring 0-4), and an additional score of 1 for visible fibrin deposition and periarticular granulocyte infiltration as described elsewhere [29]. …”

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Persistence of effector memory Th1 cells is regulated by Hopx

et al. 2010

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Th1 cells are prominent in inflamed tissue, survive conventional immunosuppression, and are believed to play a pivotal role in driving chronic inflammation. Here, we identify homeobox only protein (Hopx) as a critical and selective regulator of the survival of Th1 effector/memory cells, both in vitro and in vivo. Expression of Hopx is induced by T-bet and increases upon repeated antigenic restimulation of Th1 cells. Accordingly, the expression of Hopx is low in peripheral, naïve Th cells, but highly up-regulated in terminally differentiated effector/memory Th1 cells of healthy human donors. In murine Th1 cells, Hopx regulates the expression of genes involved in regulation of apoptosis and survival and makes them refractory to Fas-induced apoptosis. In vivo, adoptively transferred Hopxdeficient murine Th1 cells do not persist. Consequently, they cannot induce chronic inflammation in murine models of transfer-induced colitis and arthritis, demonstrating a key role of Hopx for Th1-mediated immunopathology.Key words: Cell survival . CD4 T cells . Inflammation . Memory cells Supporting Information available onlineIntroduction T-helper type 1 (Th1) cells mediate immune responses to intracellular pathogens, such as viruses, and produce IFN-g as their signature cytokine [1]. IFN-g, together with IL-12 and the transcription factors STAT1, STAT4 and T-bet, promotes the development of Th1 cells [2][3]. T-bet (T-box 21) is considered to act as the master transcription factor critically regulating Th1 lineage commitment [3][4][5]. Apart from their protective role in clearing infections, Th1 cells can initiate and maintain chronic inflammatory diseases, e.g. inflammatory bowel disease [6][7][8][9], uveitis [10], EAE [11,12] and arthritis [13]. In vitro, Th1 cells are much more sensitive to Fas-mediated apoptosis than Th2 or Th17 cells [14][15][16][17][18][19][20]. In vivo, however, effector/memory Th1 cells are abundant in chronically inflamed tissue [21][22][23] and persist over long time periods [24][25][26], suggesting that their sensitivity to Eur. J. Immunol. 2010. 40: 2993-3006 DOI 10.1002 HIGHLIGHTS 2993 FrontlineFas-mediated apoptosis is strictly regulated. Here, we demonstrate that among CD4 1 T cells, the transcriptional cofactor homeobox only protein (Hopx) is expressed by repeatedly restimulated Th1 cells, but not by Th2, Th17 or regulatory T cells. Hopx regulates Fas-mediated apoptosis of effector/memory Th1 cells and is critically required for their persistence in vivo.In vertebrates, Hopx expression originally was detected in the myocardium [27,28]. There, expression of Hopx is induced by the cardiac transcription factor Nkx2-5. Hopx-deficient mice show a complex, incompletely penetrant phenotype. Some Hopxdeficient embryos have a poorly developed myocardium with reduced cell numbers, others show normal, and still others show increased numbers of cardiomyocytes after birth [27,28]. Hopx does not bind to homeobox consensus binding sequences, and it has been postulated that Hopx acts indirectly, partnering with ...

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Section: Flow Cytometrymentioning

confidence: 99%

“…The shRNA expression vector was generated as described previously [29]. The Hopx target sequence was designed with Dharmacon siRNA Design tool (5 0 -GCAGATCTGTTACGGA-CTA-3 0 ).…”

Section: Retroviral Expression Vectors and Retroviral Infectionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Persistence of effector memory Th1 cells is regulated by Hopx

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Regulation of Fatty Acid Oxidation by Twist 1 in the Metabolic Adaptation of T Helper Lymphocytes to Chronic Inflammation

Hradilkova

Maschmeyer

Westendorf

et al. 2019

Arthritis & Rheumatology

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Objective Inflamed tissue is characterized by low availability of oxygen and nutrients. Yet CD4+ T helper lymphocytes persist over time in such tissue and probably contribute to the chronicity of inflammation. This study was undertaken to analyze the metabolic adaptation of these cells to the inflamed environment. Methods Synovial and blood CD4+ T cells isolated ex vivo from patients with juvenile idiopathic arthritis (JIA) and murine CD4+ T cells were either stimulated once or stimulated repeatedly. Their dependency on particular metabolic pathways for survival was then analyzed using pharmacologic inhibitors. The role of the transcription factor Twist 1 was investigated by determining lactate production and oxygen consumption in Twist1‐sufficient and Twist1‐deficient murine T cells. The dependency of these murine cells on particular metabolic pathways was analyzed using pharmacologic inhibitors. Results Programmed death 1 (PD‐1)+ T helper cells in synovial fluid samples from patients with JIA survived via fatty acid oxidation (mean ± SEM survival of 3.4 ± 2.85% in the presence of etomoxir versus 60 ± 7.08% in the absence of etomoxir on day 4 of culture) (P < 0.0002; n = 6) and expressed the E‐box–binding transcription factor TWIST1 (2–14‐fold increased expression) (P = 0.0156 versus PD‐1− T helper cells; n = 6). Repeatedly restimulated murine T helper cells, which expressed Twist1 as well, needed Twist1 to survive via fatty acid oxidation. In addition, Twist1 protected the cells against reactive oxygen species. Conclusion Our findings indicate that TWIST1 is a master regulator of metabolic adaptation of T helper cells to chronic inflammation and a target for their selective therapeutic elimination.

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IMprinting of PAthogenic Memory in Berlin

Romagnani¹,

Hauser²,

Chang³

2013

Eur J Immunol

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Immunological memory is not only protective against recurrent pathogens but it also contributes to the pathogenesis of chronic inflammation, especially in rheumatic diseases. The Joint Meeting of the Henry Kunkel Society (HKS) and the Research Consortium IMPAM (IMprinting of the PAthogenic Memory for rheumatic inflammation), which took place in June 2012 in Berlin, was devoted to discussing the basic mechanisms involved in the generation and maintenance of immunological memory, as well as the implications of immunological memory for the pathogenesis and therapy of rheumatic diseases, cancer and vaccine development as outlined in this Meeting Report.

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Autoregulation of Th1-mediated inflammation by twist1

Cited by 99 publications

References 47 publications

Persistence of effector memory Th1 cells is regulated by Hopx

Persistence of effector memory Th1 cells is regulated by Hopx

Regulation of Fatty Acid Oxidation by Twist 1 in the Metabolic Adaptation of T Helper Lymphocytes to Chronic Inflammation

IMprinting of PAthogenic Memory in Berlin

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