Epigenomic Profiling of Human CD4+ T Cells Supports a Linear Differentiation Model and Highlights Molecular Regulators of Memory Development

Durek, Pawel; Nordström, Karl; Gasparoni, Gilles; Salhab, Abdulrahman; Kressler, Christopher; Almeida, Melanie de; Baßler, Kevin; Ulas, Thomas; Schmidt, Florian; Xiong, Jieyi; Glažar, Petar; Klironomos, Filippos; Sinha, Anupam; Kinkley, Sarah; Yang, Xinyi; Arrigoni, Laura; Amirabad, Azim Dehghani; Ardakani, Fatemeh Behjati; Feuerbach, Lars; Gorka, Oliver; Ebert, Peter; Müller, Fabian; Li, Na; Frischbutter, Stefan; Schlickeiser, Stephan; Cendón, Carla; Fröhler, Sebastian; Felder, Bärbel; Gasparoni, Nina; Imbusch, Charles D.; Hutter, Barbara; Zipprich, Gideon; Tauchmann, Yvonne; Reinke, Simon; Wassilew, Georgi I.; Hoffmann, Ute; Richter, Andreas S.; Sieverling, Lina; Chang, Hyun‐Dong; Syrbe, Uta; Kalus, Ulrich; Eils, Jürgen; Brors, Benedikt; Manke, Thomas; Ruland, Jürgen; Lengauer, Thomas; Rajewsky, Nikolaus; Chen, Wei; Dong, Jun; Sawitzki, Birgit; Chung, Ho‐Ryun; Rosenstiel, Philip; Schulz, Marcel H.; Schultze, Joachim L.; Radbruch, Andreas; Walter, Jörn; Hamann, Alf; Polansky, Julia K.

doi:10.1016/j.immuni.2016.10.022

Cited by 183 publications

(221 citation statements)

References 63 publications

(65 reference statements)

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“…Thus, at a global level of gene expression, memory T lymphocytes of the bone marrow are dormant, and distinct from circulating memory T cells. This is confirmed, when we look not at gene expression itself, but rather at epigenetic imprinting of genes for reexpression 135. This analysis reveals a progressive global demethylation for circulating central memory, effector memory, and terminally differentiated memory cells.…”

Section: The Lifestyle Of Bone Marrow Memory T Lymphocytesmentioning

confidence: 52%

Immunological memories of the bone marrow

Chang

Tokoyoda

Radbruch

2018

Immunological Reviews

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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.

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Section: The Lifestyle Of Bone Marrow Memory T Lymphocytesmentioning

confidence: 52%

Immunological memories of the bone marrow

Chang

Tokoyoda

Radbruch

2018

Immunological Reviews

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“…As T cells develop along a linear developmental trajectory from Tn to Tcm, and then to Ttm and Temcells, they undergo progressive epigenetic remodeling, characterized by de-repression of cellular genes and loss of histone methylation islands that regulate expression of these genes (Durek et al, 2016). Thus, the pattern of HIV downregulation we observe mirrors the overall epigenetic program of these cells, suggesting a link between the two.…”

Section: Discussionmentioning

confidence: 99%

“…For example, CD4 + T cells, the major host cell for HIV infection, can exist as several different developmental stages, categorized as naive (Tn), central (Tcm) and effector memory (Tem), and effector cells. Each of these subtypes have distinct transcriptional and epigenetic programs that could affect the activity of the integrated HIV promoter (Durek et al, 2016). Additionally, biological noise and stochastic fluctuations in transcriptional activity could play an important role in either establishment or reversal of latency (Dar et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Single-Cell Analysis of Quiescent HIV Infection Reveals Host Transcriptional Profiles that Regulate Proviral Latency

et al. 2018

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SUMMARY A detailed understanding of the mechanisms that establish or maintain the latent reservoir of HIV will guide approaches to eliminate persistent infection. We used a cell line and primary cell models of HIV latency to investigate viral RNA (vRNA) expression and the role of the host transcriptome using single-cell approaches. Single-cell vRNA quantitation identified distinct populations of cells expressing various levels of vRNA, including completely silent populations. Strikingly, single-cell RNA-seq of latently infected primary cells demonstrated that HIV downregulation occurred in diverse transcriptomic environments but was significantly associated with expression of a specific set of cellular genes. In particular, latency was more frequent in cells expressing a transcriptional signature that included markers of naive and central memory T cells. These data reveal that expression of HIV proviruses within the latent reservoir are influenced by the host cell transcriptional program. Therapeutic modulation of these programs may reverse or enforce HIV latency.

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“…Butyrate strongly induces FoxP1 mRNA in both CD4 + and CD8 + lymphocytes. FoxP1 is a repressor that inhibits lymphocyte development as well as CD4 + , CD8 + , and B cell activation (Durek et al, 2016; Feng et al, 2011; Stephen et al, 2014; Wang et al, 2014; Wei et al, 2016). FoxP1 is a candidate to mediate some of the inhibitory effects of SCFA on CD4 + and CD8 + lymphocyte mediated immune response, but the role of FoxP1 induction by SCFA in the lung host microbial interface needs confirmation in animal models with cell specific conditional deletion.…”

Section: Discussionmentioning

confidence: 99%

Anaerobic Bacterial Fermentation Products Increase Tuberculosis Risk in Antiretroviral-Drug-Treated HIV Patients

Segal

Clemente

et al. 2017

Cell Host & Microbe

116

105

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Despite the immune-reconstitution with antiretroviral therapy (ART), HIV-infected individuals remain highly susceptible to tuberculosis (TB) and have an enrichment of oral anaerobes in the lung. Products of bacterial anaerobic metabolism, like butyrate and other short chain fatty acids (SCFAs), induce regulatory T cells (Tregs). We tested if SCFAs contribute to poor TB control in a longitudinal cohort of ART treated HIV-infected South Africans. Increase in serum SCFAs was associated with increased TB susceptibility. SCFAs inhibited IFN-γ and IL-17A production in peripheral blood mononuclear cells from HIV-infected ART-treated individuals in response to M. tuberculosis antigen stimulation. Pulmonary SCFAs correlated with increased oral anaerobes such as Prevotella in the lung and with M tuberculosis antigen-induced Tregs. Metabolites from anaerobic bacterial fermentation may therefore increase TB susceptibility by suppressing IFN-γ and IL-17A production during the cellular immune response to M. tuberculosis.

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Epigenomic Profiling of Human CD4+ T Cells Supports a Linear Differentiation Model and Highlights Molecular Regulators of Memory Development

Cited by 183 publications

References 63 publications

Immunological memories of the bone marrow

Immunological memories of the bone marrow

Single-Cell Analysis of Quiescent HIV Infection Reveals Host Transcriptional Profiles that Regulate Proviral Latency

Anaerobic Bacterial Fermentation Products Increase Tuberculosis Risk in Antiretroviral-Drug-Treated HIV Patients

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