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Systematic decoding of cis gene regulation defines context-dependent control of the multi-gene costimulatory receptor locus in human T cells [4C-seq]

ABSTRACT: Cis-regulatory elements (CRE) interact with trans regulators to orchestrate gene expression, but how transcriptional regulation is coordinated in multi-gene loci has not been experimentally defined. We sought to characterize the CREs controlling dynamic expression of adjacent T cell costimulatory genes CD28, CTLA4, and ICOS encoding regulators of cell-mediated immunity. Tiling CRISPR interference (CRISPRi) screens in primary human T cells – both Conventional and Regulatory subsets – uncovered gene-, cell subset- and stimulation-specific CREs. Integrating these data with CRISPR knockout (KO) screens and ATAC-seq characterization identified trans regulators influencing chromatin states at specific CRISPRi-responsive elements to control costimulatory gene expression. Lastly, we discovered and extensively validated a critical CTCF boundary that governs this locus, serving to reinforce CRE interaction with CTLA4 while also preventing promiscuous activation of CD28. By systematically mapping CREs and associated trans regulators directly in primary human T cell subsets, this work overcomes longstanding experimental limitations to decode context-dependent gene regulatory programs in a complex, multi-gene locus critical to immune homeostasis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE261328 | GEO | 2024/03/24

REPOSITORIES: GEO

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Systematic decoding of cis gene regulation defines context-dependent control of the multi-gene costimulatory receptor locus in human T cells [CRISPRi]

Project description:Cis-regulatory elements (CRE) interact with trans regulators to orchestrate gene expression, but how transcriptional regulation is coordinated in multi-gene loci has not been experimentally defined. We sought to characterize the CREs controlling dynamic expression of adjacent T cell costimulatory genes CD28, CTLA4, and ICOS encoding regulators of cell-mediated immunity. Tiling CRISPR interference (CRISPRi) screens in primary human T cells – both Conventional and Regulatory subsets – uncovered gene-, cell subset- and stimulation-specific CREs. Integrating these data with CRISPR knockout (KO) screens and ATAC-seq characterization identified trans regulators influencing chromatin states at specific CRISPRi-responsive elements to control costimulatory gene expression. Lastly, we discovered and extensively validated a critical CTCF boundary that governs this locus, serving to reinforce CRE interaction with CTLA4 while also preventing promiscuous activation of CD28. By systematically mapping CREs and associated trans regulators directly in primary human T cell subsets, this work overcomes longstanding experimental limitations to decode context-dependent gene regulatory programs in a complex, multi-gene locus critical to immune homeostasis.

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Systematic decoding of cis gene regulation defines context-dependent control of the multi-gene costimulatory receptor locus in human T cells [ATAC-seq]

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Gene expression profile of conventional T cells (Tconv) and regulatory T cells (Treg) stimulated with anti-costimulatory molecule antibodies

Project description:Co-stimulatory molecules of the CD28 family on T lymphocytes integrate cues from innate immune system sensors, and modulate activation responses in conventional CD4+ T cells (Tconv) and their FoxP3+ regulatory counterparts (Treg). To better understand how costimulatory and co-inhibitory signals might be integrated, we profiled the changes in gene expression elicited in the hours and days after engagement of Treg and Tconv by anti-CD3 and either anti-CD28, -CTLA4, -ICOS, -PD1, -BTLA or -CD80. Total CD4+ T cells were stimulated by anti-CD3 and either anti-CD28, -CTLA4, -ICOS, -PD1, -BTLA or -CD80 antibodies for 1, 4, 20 and 48 hrs and Tconv and Treg were separated by flowcytometry. The 1 and 4 hr lysates were pooled [the 'early' samples] before RNA purification and profiling, as were the 20 and 48 hr samples [the 'late' samples] (note; for Treg cells, only the 20 hr sample was used). RNA was amplified, labeled and hybridized to Mouse Gene 1.0 ST arrays with the data generation and quality control pipeline of 19 the Immunological Genome Project (www.immgen.org), in biological triplicates (duplicates only for ICOS and CD80). Raw data were background-corrected and normalized using the RMA algorithm.

2012-11-15 | E-GEOD-42276 | biostudies-arrayexpress

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Project description:CD4+ T cells recognize antigens through their T cell receptors (TCRs); however, additional signals involving costimulatory receptors, for example, CD28, are required for proper T cell activation. Alternative costimulatory receptors have been proposed, including members of the Toll-like receptor (TLR) family, such as TLR5 and TLR2. To understand the molecular mechanism underlying a potential costimulatory role for TLR5, we generated detailed molecular maps and logical models for the TCR and TLR5 signaling pathways and a merged model for cross-interactions between the two pathways. Furthermore, we validated the resulting model by analyzing how T cells responded to the activation of these pathways alone or in combination, in terms of the activation of the transcriptional regulators CREB, AP-1 (c-Jun), and NF-κB (p65). Our merged model accurately predicted the experimental results, showing that the activation of TLR5 can play a similar role to that of CD28 activation with respect to AP-1, CREB, and NF-κB activation, thereby providing insights regarding the cross-regulation of these pathways in CD4+ T cells.

2021-04-06 | MODEL1903260001 | BioModels

Rodríguez-Jorge2019 - Boolean model of combined TCR and TLR5 signaling for CD4 + T cell activation

2021-04-06 | MODEL1903260003 | BioModels

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Project description:We observed self-activation of SKM-CAR-T cells which target novel mesothelioma antigen. CAR-T with CD28 costimulatory domain showed signs of exhaustion while those with 4-1BB costimulatory domain did not. To elucidate molecules responsible for self-activation-induced exhaustion, we performed RNA-seq analysis of SKM-CAR-T cells with CD28 or 4-1BB and CD19-CAR-T cells with CD28 or 4-1BB.

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Chimeric Antigen Receptors with a MyD88 and CD40 costimulatory endodomain endow T cells with superior antitumor activity

Project description:CAR T-cell therapy for solid tumors has shown limited efficacy in early phase clinical studies. The majority of CARs encode CD28 and/or 41BB costimulatory endodomains and we explored here if MyD88 and CD40 (MC) costimulatory endodomains in CARs improve their antitumor activity. We generated CD28-, 41BB-, and MC-CAR T-cells and demonstrate that MC-CAR T-cells have greater proliferative capacity and antitumor activity in repeat stimulation assays and in tumor models in vivo. Transcriptomic analysis revealed that MC-CAR T-cells expressed higher levels of MYB and FOXM1, key cell cycle regulators, and are activated at base line. After stimulation, MC-CAR T-cells remain in a less differentiated state than CD28- and 41BB-CAR T-cells as judged by low levels of TBET and BLIMP1 expression, and lower cytolytic activity in comparison to CD28- and 41BB-CAR T-cells. Thus, including MyD88 and CD40 signaling domains in CARs may improve current CAR T-cell therapy approaches for solid tumors.

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