Cell Granularity Reflects Immune Cell Function and Enables Selection of Lymphocytes with Superior Attributes for Immunotherapy

Wu, Tongjin; Tan, Joel Heng Loong; Sin, Wei-Xiang; Luah, Yen Hoon; Tan, Sue Yee; Goh, M. Cynthia; Birnbaum, Michael E.; Chen, Qingfeng; Cheow, Lih Feng

doi:10.1002/advs.202302175

Cited by 4 publications

(1 citation statement)

References 66 publications

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“…Non-rod retinal cells also contain a wide range of nuclear organization and granularity [39] , harboring 1-5 chromocenters of various sizes (Figure 1B and C). Immune cells are well studied for their diverse nuclear organization and granularity, which reflects distinct functions and differentiation states [40] . Whether cells with high levels of chromatin segregation and low nuclear granularity share similar architectural protein functions with rods to regulate global transcription remains unknown.…”

Section: Rods As a Model To Study Transcription And Nuclear Architecturementioning

confidence: 99%

CTCF regulates global chromatin accessibility and transcription during rod photoreceptor development

Chen,

Keremane,

Wang

et al. 2024

Preprint

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Chromatin architecture facilitates accurate transcription at a number of loci, but it remains unclear how much chromatin architecture is involved in global transcriptional regulation. Previous work has shown that rapid depletion of the architectural protein CTCF in cell culture strongly alters chromatin organization but results in surprisingly limited gene expression changes. This discrepancy has also been observed when other architectural proteins are depleted, and one possible explanation is that full transcriptional changes are masked by cellular heterogeneity. We tested this idea by performing multi-omics analyses with sorted post-mitotic mouse rods, which undergo synchronized development, and identified CTCF-dependent regulation of global chromatin accessibility and gene expression. Depletion of CTCF leads to dysregulation of ∼20% of the entire transcriptome (>3,000 genes) and ∼41% of genome accessibility (>26,000 sites), and these regions are strongly enriched in euchromatin. Importantly, these changes are highly enriched for CTCF occupancy, suggesting direct CTCF binding and transcriptional regulation at these active loci. CTCF mainly promotes chromatin accessibility of these direct binding targets, and a large fraction of these sites correspond to promoters. At these sites, CTCF binding frequently promotes accessibility and inhibits expression, and motifs of transcription repressors are found to be significantly enriched. Our findings provide different and often opposite conclusions from previous studies, emphasizing the need to consider cell heterogeneity and cell type specificity when performing multi-omics analyses. We conclude that the architectural protein CTCF binds chromatin and regulates global chromatin accessibility and transcription during rod development.

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Section: Rods As a Model To Study Transcription And Nuclear Architecturementioning

confidence: 99%

CTCF regulates global chromatin accessibility and transcription during rod photoreceptor development

Chen,

Keremane,

Wang

et al. 2024

Preprint

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Deep learning pipeline for automated cell profiling from cyclic imaging

Landeros,

Oh,

Weissleder

et al. 2024

Sci Rep

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Cyclic fluorescence microscopy enables multiple targets to be detected simultaneously. This, in turn, has deepened our understanding of tissue composition, cell-to-cell interactions, and cell signaling. Unfortunately, analysis of these datasets can be time-prohibitive due to the sheer volume of data. In this paper, we present CycloNET, a computational pipeline tailored for analyzing raw fluorescent images obtained through cyclic immunofluorescence. The automated pipeline pre-processes raw image files, quickly corrects for translation errors between imaging cycles, and leverages a pre-trained neural network to segment individual cells and generate single-cell molecular profiles. We applied CycloNET to a dataset of 22 human samples from head and neck squamous cell carcinoma patients and trained a neural network to segment immune cells. CycloNET efficiently processed a large-scale dataset (17 fields of view per cycle and 13 staining cycles per specimen) in 10 min, delivering insights at the single-cell resolution and facilitating the identification of rare immune cell clusters. We expect that this rapid pipeline will serve as a powerful tool to understand complex biological systems at the cellular level, with the potential to facilitate breakthroughs in areas such as developmental biology, disease pathology, and personalized medicine.

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Mechanical forces amplify TCR mechanotransduction in T cell activation and function

Jeffreys,

Brockman,

Zhai

et al. 2024

Applied Physics Reviews

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Adoptive T cell immunotherapies, including engineered T cell receptor (eTCR) and chimeric antigen receptor (CAR) T cell immunotherapies, have shown efficacy in treating a subset of hematologic malignancies, exhibit promise in solid tumors, and have many other potential applications, such as in fibrosis, autoimmunity, and regenerative medicine. While immunoengineering has focused on designing biomaterials to present biochemical cues to manipulate T cells ex vivo and in vivo, mechanical cues that regulate their biology have been largely underappreciated. This review highlights the contributions of mechanical force to several receptor–ligand interactions critical to T cell function, with central focus on the TCR–peptide-loaded major histocompatibility complex (pMHC). We then emphasize the role of mechanical forces in (i) allosteric strengthening of the TCR–pMHC interaction in amplifying ligand discrimination during T cell antigen recognition prior to activation and (ii) T cell interactions with the extracellular matrix. We then describe approaches to design eTCRs, CARs, and biomaterials to exploit TCR mechanosensitivity in order to potentiate T cell manufacturing and function in adoptive T cell immunotherapy.

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Cell Granularity Reflects Immune Cell Function and Enables Selection of Lymphocytes with Superior Attributes for Immunotherapy

Cited by 4 publications

References 66 publications

CTCF regulates global chromatin accessibility and transcription during rod photoreceptor development

CTCF regulates global chromatin accessibility and transcription during rod photoreceptor development

Deep learning pipeline for automated cell profiling from cyclic imaging

Mechanical forces amplify TCR mechanotransduction in T cell activation and function

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