Transcription Factor 7 Limits Regulatory T Cell Generation in the Thymus

Barra, Melanie M.; Richards, David M.; Hansson, Jenny; Hofer, Ann Cathrin; Delacher, Michael; Hettinger, Jan; Krijgsveld, Jeroen; Feuerer, Markus

doi:10.4049/jimmunol.1500821

Cited by 35 publications

(33 citation statements)

References 52 publications

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“…First, the proteome analyses determined largely identical abundances of TCR signalling components within Treg cells and Tconv cells. This observation is widely in line with recent data from proteome studies of human and murine Treg cells, although those studies did not specifically focus on TCR signalling . The present proteomic approach identified low abundance of Themis in Treg cells, a molecule known to play a role in the early LAT signalosome in Tconv cells .…”

Section: Discussionsupporting

confidence: 88%

“…3 and Supporting Information Table 1). Cross‐inspection of our data with former published proteomic studies could now substantiate a series of proteins with Treg cell‐specific abundances, although these proteins are not described to be directly involved in TCR signalling. This includes Helios, Aiolos, Sortin nexin‐18, Ergic1, Annexin A4, CAPG, Stim2, NDRG1, Ladinin‐1, Niban, S100A4 and Reticulocalbin‐1 (Supporting Information Table 1).…”

Section: Resultsmentioning

confidence: 52%

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TCR signalling network organization at the immunological synapses of murine regulatory T cells

et al. 2017

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Regulatory T (Treg) cells require T-cell receptor (TCR) signalling to exert their immunosuppressive activity, but the precise organization of the TCR signalling network compared to conventional T (Tconv) cells remains elusive. By using accurate mass spectrometry and multi-epitope ligand cartography (MELC) we characterized TCR signalling and recruitment of TCR signalling components to the immunological synapse (IS) in www.eji-journal.euThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. 2Marco van Ham et al. Eur. J. Immunol. 2017. 0: 1-16 in Treg cells, thereby, seems to be differentially organized as in Tconv cells: Treg cells show reduced Ca 2+ flux and ERK1/2 phosphorylation upon TCR stimulation [6][7][8], and downstream signalling molecules such as Lck, LAT and PLCγ1 are essential for Treg cell suppressive capacity [9,10]. In this line, a novel TCRmediated ADAP/integrin-independent PLCγ1 activation pathway was described to be required for suppression of Tconv cells by Treg cells [11]. Furthermore, Treg cells exhibit reduced S473 phosphorylation of Akt which seems a prerequisite for suppression [12]. Although the enzymatic activity of the tyrosine kinase ZAP70 seems to be dispensable for the suppressive phenotype of Foxp3 + Treg cells [13], a single mutation within the SH2-domain of ZAP70 leads to impaired suppressive activities, which indicated its importance at the immunological synapse (IS) [14]. Finally, it has only recently been recognized that the recruitment of TCR signalling components into the IS is differentially organized in Treg cells and Tconv cells. The protein kinase PKCθ is recruited to the IS in Tconv cells, in Treg cells, however, this kinase was found to be sequestered away from the IS, but still of importance to control suppression [15]. The spatial recruitment of signalling components during IS formation critically depends on cytoskeleton dynamics, which in turn is controlled by TCR activation and subsequent phosphorylation of proteins regulating cytoskeleton reorganization [5]. As part of these processes the microtubule-organizing centre (MTOC) is rapidly translocated in proximity to the IS. MTOC repositioning depends on LAT, ZAP70 and SLP76 [16] and is regulated by a cascade of distinct isoforms of the family of novel protein kinase C (nPKC) [17]. The MTOC serves as a platform to coordinate molecular movements from and to the IS through the support of microtubule (MT) motors [18]. For instance, TCR microclusters move along MTs towards the centre of the IS in a dynein-dependent manner [19], and hindrance of MTOC polarization, molecular transport and cytoskeleton dynamics prevent proper propagation of TCR signals [20].It is now tempting to speculate that the localization of signalling modules within the IS may be instrumental for the formation of a Treg cell-specific IS and the suppressive phenotype of Treg cells. At this moment, however,...

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Section: Discussionsupporting

confidence: 88%

Section: Resultsmentioning

confidence: 52%

TCR signalling network organization at the immunological synapses of murine regulatory T cells

et al. 2017

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“…Actually, we investigated whether the enrichment in Penk at the genetic level would also be seen at the protein level. Deceptively, Penk was not listed in 2 different databases reporting the proteomes of murine Treg or Tconv [31,32]. We believe this observation reflects technical issues related to mass spectrometry rather than a "real" negative result contradicting our analysis.…”

Section: Discussionmentioning

confidence: 74%

Characterization of a regulatory T cells molecular meta-signature identifies the pro-enkephalin gene as a novel marker in mice

Aubert

Salomon

Marodon

2019

Preprint

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Regulatory T cells (Treg) are crucial in the proper balance of the immune system. A better characterization of Treg-specific genes should extend our knowledge on their complex biology. However, to date there is no consensual Treg signature in the literature. Here, we extracted a molecular Treg meta-signature relative to CD4+ conventional T cell from 8 different but comparable publicly available microarray datasets. We confirmed the validity of our result using the much larger but less stringent Immuno-Navigator database. However, many genes of the Treg meta-signature were also expressed at the protein level by other immune cell subsets, as assessed by mass cytometry, with the noticeable exceptions of Il2ra, Ctla4, and Tnfrsf9. Surprisingly, the proenkephalin (Penk) gene was a prominent member of this restricted Treg meta-signature. Further analysis of public datasets and of our own RNA sequencing experiments confirms that Penk was over expressed by Treg in various murine tissues, including thymic Treg. Interestingly, Penk expression was increased in intra tumoral Treg whereas it was down modulated in the central nervous system of mice suffering from EAE. Finally, we propose a mechanistic model linking TNFR signaling and the transcription factor Batf in the regulation of Penk expression in Treg. Altogether, our results provide the first Treg meta-signature in mice and identifies Penk as a novel and unexpected Treg marker.

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“…It is also noteworthy that R24Tg mice harbored increased thymic Treg cells as opposed to the reduced number observed in R27Tg mice (14). A recent report has suggested a regulatory role of TCF1 in limiting thymic Treg cell development (21). It is thus plausible that miR-24 could also promote thymic Treg cell generation through targeting TCF1 and further suggests that miR-24 might act more as a positive player rather than a negative regulator like miR-27 in controlling Treg cell biology.…”

Section: Discussionmentioning

confidence: 99%

A Novel miR-24–TCF1 Axis in Modulating Effector T Cell Responses

Cho

Nguyen

et al. 2017

The Journal of Immunology

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miR-23~27~24 was recently implicated in restricting Th2 immunity as well as the differentiation and function of other effector T cell lineages. Interestingly, miR-24, unlike other family members, actually promotes Th1 and Th17 responses. Here, we show that miR-24 drives the production of IFNγ and IL-17 in T cells at least in part through targeting TCF1, a transcription factor known for its role in limiting Th1 and Th17 immunity. Surprisingly, while TCF1 was previously shown to promote Th2 responses through inducing GATA3, enforced TCF1 expression in miR-24-overexpresing T cells led to further downregulation of IL-4 and GATA3 expression, suggesting miR-24-mediated inhibition of Th2 immunity cannot be attributed to TCF1 repression by miR-24. Together, our data demonstrates a novel miR-24-TCF1 pathway in controlling effector cytokine production by T cells and further suggests miR-24 could function as a key upstream molecule regulating TCF1-mediated immune responses.

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Transcription Factor 7 Limits Regulatory T Cell Generation in the Thymus

Cited by 35 publications

References 52 publications

TCR signalling network organization at the immunological synapses of murine regulatory T cells

TCR signalling network organization at the immunological synapses of murine regulatory T cells

Characterization of a regulatory T cells molecular meta-signature identifies the pro-enkephalin gene as a novel marker in mice

A Novel miR-24–TCF1 Axis in Modulating Effector T Cell Responses

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