Histone H1 depletion triggers an interferon response in cancer cells via activation of heterochromatic repeats

Histone H1 has seven variants in human somatic cells and contributes to chromatin compaction and transcriptional regulation. Knock-down (KD) of each H1 variant in breast cancer cells results in altered gene expression and proliferation differently in a variant specific manner with H1.2 and H1.4 KDs being most deleterious. Here we show combined depletion of H1.2 and H1.4 has a strong deleterious effect resulting in a strong interferon (IFN) response, as evidenced by an up-regulation of many IFN-stimulated genes (ISGs) not seen in individual nor in other combinations of H1 variant KDs. Although H1 participates to repress ISG promoters, IFN activation upon H1.2 and H1.4 KD is mainly generated through the activation of the IFN response by cytosolic nucleic acid receptors and IFN synthesis, and without changes in histone modifications at induced ISG promoters. H1.2 and H1.4 co-KD also promotes the appearance of accessibility sites genome wide and, particularly, at satellites and other repeats. The IFN response may be triggered by the expression of noncoding RNA generated from heterochromatic repeats or endogenous retroviruses upon H1 KD. In conclusion, redundant H1-mediated silencing of heterochromatin is important to maintain cell homeostasis and to avoid an unspecific IFN response

SARS-CoV-2 in severe COVID-19 induces a TGF-β-dominated chronic immune response that does not target itself

The pathogenesis of severe COVID-19 reflects an inefficient immune reaction to SARS-CoV-2. Here we analyze, at the single cell level, plasmablasts egressed into the blood to study the dynamics of adaptive immune response in COVID-19 patients requiring intensive care. Before seroconversion in response to SARS-CoV-2 spike protein, peripheral plasmablasts display a type 1 interferon-induced gene expression signature; however, following seroconversion, plasmablasts lose this signature, express instead gene signatures induced by IL-21 and TGF-β, and produce mostly IgG1 and IgA1. In the sustained immune reaction from COVID-19 patients, plasmablasts shift to the expression of IgA2, thereby reflecting an instruction by TGF-β. Despite their continued presence in the blood, plasmablasts are not found in the lungs of deceased COVID-19 patients, nor does patient IgA2 binds to the dominant antigens of SARS-CoV-2. Our results thus suggest that, in severe COVID-19, SARS-CoV-2 triggers a chronic immune reaction that is instructed by TGF-β, and is distracted from itself

Multiplexed histology of COVID-19 post-mortem lung samples - CONTROL CASE 1 FOV3

Image-based data set of a post-mortem lung sample from a non-COVID-related pneumonia donor (CONTROL CASE 1 FOV3) Each image shows the same field of view (FOV), sequentially stained with the depicted fluorescence-labelled antibodies, including surface proteins, intracellular proteins and transcription factors. Images contain 2024 x 2024 pixels and are generated using an inverted wide-field fluorescence microscope with a 20x objective, a lateral resolution of 325 nm and an axial resolution above 5 µm. Images have been normalized and intensities adjusted.Funding: Deutsche Forschungsgemeinschaft HA5354/10-1, SPP1937 (HA5354/8-2) and TRR130 P17 and C01 (to Anja Hauser

Entschlüsselung von gewebsspezifischen Signalen und molekularen Mechanismen unter der Kontrolle von TH17 Zellen

TH17 cells are major drivers of inflammation and are involved in several autoimmune diseases. Tissue inflammation is a beneficial host response to infection but, when deregulated, can also contribute to autoimmunity. The crosstalk between the inflamed tissue and the immune system during an inflammatory response is the key for preserving tissue integrity and to maintain physiological processes. However, how the inflamed tissue is able to regulate the magnitude of an immune response by controlling pro-inflammatory T cells is not well characterized. In addition, during the resolution of tissue inflammation several antigen presenting cells (APCs) with tolerogenic properties are known to further push the system back to homeostasis through the expression of anti-inflammatory mediators that ultimately influence T cell fate. Here, we show that intestinal epithelial cells (IEC) are the main source of the alarmin interleukin-33 (IL-33) upon T cell dependent intestinal inflammation and that TH17 cells express the IL-33 receptor (ST2) in vivo. Also, we show that monocytes repopulating the lamina propria (LP) during the resolution of inflammation are the main source of Oncostatin (OSM) and that TH17 cells express the OSM receptor (OSMRβ). Both IL-33 and OSM promote a reduced expression of pro-inflammatory genes (Tbx21, Ifng and Csf2) and induce the expression of the anti-inflammatory gene Il10 in mouse and human TH17 cells. In vivo experiments performed with St2-/- mice demonstrate that IL-33 signaling limits the pro-inflammatory capacity of TH17 cells in the small intestine (SI) upon acute inflammation, thereby ameliorating the clinical course. Similarly, in vivo experiments performed with Experimental Autoimmune Encephalomyelitis (EAE)-induced mice demonstrate that OSM also restrains TH17 pathogenicity, thereby attenuating disease severity. Finally, we show that pro-inflammatory TH17 cells acquire a regulatory phenotype with immune- suppressive properties in response to both IL-33 and OSM. Our results provide new insights into the mechanisms by which IEC, via IL-33/ST2 axis, and monocytes, via OSM/OSMRβ axis, may control pro-inflammatory TH17 cells in the small intestine in order to sustain homeostasis.TH17-Zellen spielen eine große Rolle bei Entzündungen und sind in einigen Autoimmunerkrankungen involviert. Die Entzündungsreaktion im Gewebe ist eine protektive Antwort des Organismus auf Infektionen, kann allerdings, wenn sie fehlreguliert ist, auch zur Autoimmunität führen. Während einer Immunantwort ist der Austausch zwischen dem entzündlichen Gewebe und dem Immunsystem der Schlüssel, um die Gewebeintegrität zu erhalten und physiologische Prozesse aufrechtzuerhalten. Wie das inflammatorische Gewebe das Ausmaß der Immunreaktion durch die Kontrolle von proinflammatorischen T-Zellen reguliert, ist nicht genau charakterisiert. Zusätzlich sind einige Antigen-präsentierende Zellen (APCs) bekannt, die zum Rückgang einer Gewebeentzündung und zur Wiederherstellung der Homöostase durch deren Expression von antiinflammatorischen Mediatoren führen, und schließlich das Schicksal der T-Zellen beeinflussen. Hier konnten wir zeigen, dass intestinale Epithelzellen (IEC) die größte Quelle für das Alarmin Interleukin-33 (IL-33) nach einer T -Zell-abhängigen Inflammation ist und dass TH17-Zellen den IL-33-Rezeptor (ST2) in vivo exprimieren. Daneben konnten wir zeigen, dass Monozyten, die die Lamina propria (LP) während des Rückgangs der Entzündung neu besiedeln, die Hauptquelle für Oncostatin (OSM) sind und dass TH17-Zellen den OSM-Rezeptor (OSMRβ) exprimieren. IL-33 und OSM reduzieren beide die Expression von proinflammatorischen Genen (Tbx21, Ifng und Csf2) und induzieren die Expression des antiinflammatorischen Gens Il10 in der Maus und in humanen TH17-Zellen. In vivo-Experimente, die in St2-/--Mäusen durchgeführt wurden, zeigten, dass IL-33-Signale die proinflammatorischen Kapazitäten von TH17-Zellen im Dünndarm nach akuter Entzündung limitieren, und somit den klinischen Verlauf positiv beeinflussen. Passend dazu zeigten in vivo- Experimente in Mäusen, in denen experimentelle autoimmune Enzephalomyelitis (EAE) induziert wurde, dass OSM auch die TH17-Pathogenität eindämmt, und folglich die Schwere der Erkrankung reduziert. Schließlich zeigen wir, dass sich während der Antwort auf IL-33 und OSM proinflammatorische TH17-Zellen entwickeln, die einen regulatorischen Phänotyp mit immunsuppressiven Eigenschaften aufweisen. Unsere Ergebnisse liefern neue Einblicke in den Mechanismus, wie IEC über die IL-33/ST-Achse und wie Monozyten über die OSM /OSMRβ-Achse proinflammatorische TH17-Zellen im Dünndarm kontrollieren könnten, um die Homöostase aufrechtzuerhalten

Multiplexed histology of COVID-19 post-mortem lung samples - CONTROL CASE 2 FOV1

Image-based data set of a post-mortem lung sample from a non-COVID-19-related pneumonia donor (CONTROL CASE 2 FOV1) Each image shows the same field of view (FOV), sequentially stained with the depicted fluorescence-labelled antibodies, including surface proteins, intracellular proteins and transcription factors. Images contain 2024 x 2024 pixels and are generated using an inverted wide-field fluorescence microscope with a 20x objective, a lateral resolution of 325 nm and an axial resolution above 5 µm. Images have been normalized and intensities adjusted.Funding: Deutsche Forschungsgemeinschaft HA5354/10-1, SPP1937 (HA5354/8-2) and TRR130 P17 and C01 (to Anja Hauser

Multiplexed histology of COVID-19 post-mortem lung samples - ACUTE CASE 3 FOV2

Image-based data set of a post-mortem lung sample from a COVID-19 donor (ACUTE CASE 3 FOV2) Each image shows the same field of view (FOV), sequentially stained with the depicted fluorescence-labelled antibodies, including surface proteins, intracellular proteins and transcription factors. Images contain 2024 x 2024 pixels and are generated using an inverted wide-field fluorescence microscope with a 20x objective, a lateral resolution of 325 nm and an axial resolution above 5 µm. Images have been normalized and intensities adjusted.Funding: Deutsche Forschungsgemeinschaft HA5354/10-1, SPP1937 (HA5354/8-2) and TRR130 P17 and C01 (to Anja Hauser

Multiplexed histology of COVID-19 post-mortem lung samples - PROLONGED CASE 1 FOV1

Image-based data set of a post-mortem lung sample from a COVID-19 donor (PROLONGED CASE 1 FOV1) Each image shows the same field of view (FOV), sequentially stained with the depicted fluorescence-labelled antibodies, including surface proteins, intracellular proteins and transcription factors. Images contain 2024 x 2024 pixels and are generated using an inverted wide-field fluorescence microscope with a 20x objective, a lateral resolution of 325 nm and an axial resolution above 5 µm. Images have been normalized and intensities adjusted.Funding: Deutsche Forschungsgemeinschaft HA5354/10-1, SPP1937 (HA5354/8-2) and TRR130 P17 and C01 (to Anja Hauser

Multiplexed histology of COVID-19 post-mortem lung samples - ACUTE CASE 2 FOV3

Image-based data set of a post-mortem lung sample from a COVID-19 donor (ACUTE CASE 2 FOV3) Each image shows the same field of view (FOV), sequentially stained with the depicted fluorescence-labelled antibodies, including surface proteins, intracellular proteins and transcription factors. Images contain 2024 x 2024 pixels and are generated using an inverted wide-field fluorescence microscope with a 20x objective, a lateral resolution of 325 nm and an axial resolution above 5 µm. Images have been normalized and intensities adjusted.Funding: Deutsche Forschungsgemeinschaft HA5354/10-1, SPP1937 (HA5354/8-2) and TRR130 P17 and C01 (to Anja Hauser

Multiplexed histology of COVID-19 post-mortem lung samples - PROLONGED CASE 3 FOV1

Image-based data set of a post-mortem lung sample from a COVID-19 donor (PROLONGED CASE 3 FOV1) Each image shows the same field of view (FOV), sequentially stained with the depicted fluorescence-labelled antibodies, including surface proteins, intracellular proteins and transcription factors. Images contain 2024 x 2024 pixels and are generated using an inverted wide-field fluorescence microscope with a 20x objective, a lateral resolution of 325 nm and an axial resolution above 5 µm. Images have been normalized and intensities adjusted.Funding: Deutsche Forschungsgemeinschaft HA5354/10-1, SPP1937 (HA5354/8-2) and TRR130 P17 and C01 (to Anja Hauser

Multiplexed histology of COVID-19 post-mortem lung samples - CONROL CASE 3 FOV2

Image-based data set of a post-mortem lung sample from a COVID-19 donor (CONTROL CASE 3 FOV2) Each image shows the same field of view (FOV), sequentially stained with the depicted fluorescence-labelled antibodies, including surface proteins, intracellular proteins and transcription factors. Images contain 2024 x 2024 pixels and are generated using an inverted wide-field fluorescence microscope with a 20x objective, a lateral resolution of 325 nm and an axial resolution above 5 µm. Images have been normalized and intensities adjusted.Funding: Deutsche Forschungsgemeinschaft HA5354/10-1, SPP1937 (HA5354/8-2) and TRR130 P17 and C01 (to Anja Hauser