Genome-wide DNA-methylation landscape defines specialization of regulatory T cells in tissues

Delacher, Michael; Imbusch, Charles D.; Weichenhan, Dieter; Breiling, Achim; Hotz‐Wagenblatt, Agnes; Träger, Ulrike; Hofer, Ann Cathrin; Kägebein, Danny; Wang, Qi; Frauhammer, Felix; Mallm, Jan‐Philipp; Bauer, Katharina; Herrmann, Carl; Lang, Philipp A.; Brors, Benedikt; Plass, Christoph; Feuerer, Markus

doi:10.1038/ni.3799

Cited by 216 publications

(245 citation statements)

References 49 publications

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“…Interestingly, the frequency of iTregs that do not express both Helios and Nrp1 (Helios and Nrp double-negative iTregs) appeared to be decreased (Figure S5). As BATF and BATF3 are involved in regulating a myriad of genes (Delacher et al, 2017; Hayatsu et al, 2017; Vasanthakumar et al, 2015), it is possible that in BATF3- and BATF-deficient iTregs, Nrp1 expression may be impacted, resulting in such discrepancies. We performed additional experiments addressing the role of sodium butyrate in Foxp3 induction in BATF and BATF3 double-deficient T cells.…”

Section: Resultsmentioning

confidence: 99%

OX40 Costimulation Inhibits Foxp3 Expression and Treg Induction via BATF3-Dependent and Independent Mechanisms

et al. 2018

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SUMMARY Naive CD4+ T cells can be converted to Foxp3+ T regulatory cells (Tregs) in the periphery (iTregs), where induction of Foxp3 gene expression is central to Treg differentiation. OX40 signaling is known to inhibit Foxp3 expression and Treg induction, but the underlying mechanisms remain poorly defined. Here, we found that OX40 costimulation activates two distinct molecular pathways to suppress Foxp3 expression in freshly activated naive CD4+ T cells. Specifically, OX40 upregulates BATF3 and BATF, which produce a closed chromatin configuration to repress Foxp3 expression in a Sirt1/7-dependent manner. Moreover, OX40 can also activate the AKT-mTOR pathway, especially in the absence of BATF3 and BATF, to inhibit Foxp3 induction, and this is mediated by phos-phorylation and nuclear exclusion of the transcription factor Foxo1. Taken together, our results provide key mechanistic insights into how OX40 inhibits Foxp3 expression and Treg induction in the periphery.

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Section: Resultsmentioning

confidence: 99%

OX40 Costimulation Inhibits Foxp3 Expression and Treg Induction via BATF3-Dependent and Independent Mechanisms

et al. 2018

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“…The signals driving lung tissue-specific CD4 + T-cell development remain largely unknown, but antigen exposure leading to T-cell receptor agonism could induce chromatin changes responsible for the maturation process. Tcell receptor-dependent chromatin state alterations dominate the epigenetic landscape during thymic CD4 + T-cell development (23,25); similar processes may continue to establish tissue-specific immunity (32). Differing metabolic requirements and profiles could also contribute to the maturation phenotype with a possible mechanistic link to differential CpG methylation patterns (33).…”

Section: Discussionmentioning

confidence: 99%

DNA methylation regulates the neonatal CD4+ T-cell response to pneumonia in mice

McGrath‐Morrow

Ndeh

Helmin

et al. 2018

Journal of Biological Chemistry

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“…Changes in transcription strongly underlie the stability of the immunosuppressive Treg programme. Factors controlling Treg transcription, both transcription factors and the chromatin landscape, act in an independent and overlapping fashion to establish and maintain the Treg programme upon activation . TI‐Tregs exhibit a distinctive transcriptional programme compared with Tregs in other sites of the body, opening up the possibility to specifically disrupt the TI‐Treg transcriptome as a mechanism to enhance antitumour immunity …”

Section: Transcription In Ti‐tregmentioning

confidence: 99%

Treg programming and therapeutic reprogramming in cancer

Ayala

DuPage

2019

Immunology

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Summary Overcoming the immunosuppressive tumour microenvironment is the major challenge impeding cancer immunotherapy today. Regulatory T‐cells (Tregs) are prevalent in nearly all cancers and, as immunosuppressive regulators of immune responses, they are the principal opponents of cancer immunotherapy. However, disabling Tregs systemically causes severe autoimmune toxicity, hastening the need for more selective methods to target intratumoural Tregs. In this review, we discuss a burgeoning new modality to specifically target tumour‐infiltrating Tregs (TI‐Tregs) by reprogramming their functionality from immunosuppressive to immune stimulatory within tumours. As the basis for therapeutic selectivity of TI‐Tregs, we will focus on the defining features of Tregs within cancer: their highly activated state controlled by the engagement of key surface receptors, their distinct metabolic programme, and their unique transcriptional programme. By identifying proteins and pathways that distinguish TI‐Tregs from other Tregs in the body, as well as from the beneficial antitumour effector T‐cells within tumours, we highlight mechanisms to selectively reprogramme TI‐Tregs for the treatment of cancer.

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Genome-wide DNA-methylation landscape defines specialization of regulatory T cells in tissues

Cited by 216 publications

References 49 publications

OX40 Costimulation Inhibits Foxp3 Expression and Treg Induction via BATF3-Dependent and Independent Mechanisms

OX40 Costimulation Inhibits Foxp3 Expression and Treg Induction via BATF3-Dependent and Independent Mechanisms

DNA methylation regulates the neonatal CD4+ T-cell response to pneumonia in mice

Treg programming and therapeutic reprogramming in cancer

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