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Tissue-specific transcriptional imprinting and heterogeneity in human innate lymphoid cells revealed by full-length single-cell RNA-sequencing.

ABSTRACT: The impact of the microenvironment on innate lymphoid cell (ILC)-mediated immunity in humans remains largely unknown. Here we used full-length Smart-seq2 single-cell RNA-sequencing to unravel tissue-specific transcriptional profiles and heterogeneity of CD127⁺ ILCs across four human tissues. Correlation analysis identified gene modules characterizing the migratory properties of tonsil and blood ILCs, and signatures of tissue-residency, activation and modified metabolism in colon and lung ILCs. Trajectory analysis revealed potential differentiation pathways from circulating and tissue-resident naïve ILCs to a spectrum of mature ILC subsets. In the lung we identified both CRTH2⁺ and CRTH2^- ILC2 with lung-specific signatures, which could be recapitulated by alarmin-exposure of circulating ILC2. Finally, we describe unique TCR-V(D)J-rearrangement patterns of blood ILC1-like cells, revealing a subset of potentially immature ILCs with TCR-δ rearrangement. Our study provides a useful resource for in-depth understanding of ILC-mediated immunity in humans, with implications for disease.

SUBMITTER: Mazzurana L

PROVIDER: S-EPMC8089104 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Tissue-specific transcriptional imprinting and heterogeneity in human innate lymphoid cells revealed by full-length single-cell RNA-sequencing

Project description:The impact of the microenvironment on innate lymphoid cell (ILC)-mediated immunity in humans remains largely unknown. Here we used full-length Smart-seq2 single-cell RNA-sequencing to unravel tissue-specific transcriptional profiles and heterogeneity of CD127+ ILCs across four human tissues. Correlation analysis identified gene modules characterizing the migratory properties of tonsil and blood ILCs, and signatures of tissue-residency, activation and modified metabolism in gut and lung ILCs. Trajectory analysis revealed potential differentiation pathways from circulating and tissue-resident naïve ILCs to a spectrum of mature ILC subsets. In the lung we identified both CRTH2+ and CRTH2- ILC2 with lung-specific signatures, which could be recapitulated by alarmin-exposure of circulating ILC2. Finally, we describe unique TCR-V(D)J-rearrangement patterns of blood ILC1-like cells, revealing a subset of potentially immature ILCs with TCR-d rearrangement. In summary, we provide publicly available data as a resource for in-depth understanding of ILC-mediated immunity in humans, with implications for disease.

2020-12-14 | GSE150050 | GEO

Tissue-specific transcriptional imprinting and heterogeneity in human innate lymphoid cells revealed by full-length single-cell RNA-sequencing

Project description:Tissue-specific transcriptional imprinting and heterogeneity in human innate lymphoid cells revealed by full-length single-cell RNA-sequencing

| PRJNA630996 | ENA

Tissue-specific transcriptional profiles and heterogeneity of natural killer cells and group 1 innate lymphoid cells.

Project description:Natural killer (NK) cells and type 1 innate lymphoid cells (ILC1s) are populations of non-T, non-B lymphocytes in peripheral tissues. Although NK and ILC1 subsets have been described, their identification and characteristics remain unclear. We performed single-cell RNA sequencing and CITE-seq to explore NK and ILC1 heterogeneity between tissues. We observed that although NK1 and NK2 subsets are conserved in spleen and liver, ILC1s are heterogeneous across tissues. We identified sets of genes expressed by related subsets or characterizing unique ILC1 populations in each organ. The syndecan-4 appeared as a marker discriminating murine ILC1 from NK cells across organs. Finally, we revealed that the expressions of EOMES, GZMA, IRF8, JAK1, NKG7, PLEK, PRF1, and ZEB2 define NK cells and that IL7R, LTB, and RGS1 differentiate ILC1s from NK cells in mice and humans. Our data constitute an important resource to improve our understanding of NK-ILC1 origin, phenotype, and biology.

| S-EPMC9729827 | biostudies-literature

Single cell RNA sequencing reveals regional heterogeneity of hepatobiliary innate lymphoid cells in a tissue-enriched fashion.

Project description:IL-33 promotes type 2 immunity, epithelial repair, and tissue fibrosis by activating group 2 innate lymphoid cells (ILC2). ILC2 lack all known surface markers of mature T, B, NK, and myeloid cell lineages (Linneg), express the IL-33 receptor ST2, and release type 2 cytokines which contribute to cholangiocyte proliferation and activation of hepatic stellate cells. This pathway results in massive proliferation of the extrahepatic bile duct (EHBD) but also exacerbates liver fibrosis, suggesting that there may be tissue-specific subpopulations of IL-33-induced ILC. To determine the tissue-specific subsets of ILC in the hepatobiliary system, we analyzed CD45+Linneg mononuclear cells from IL-33 treated adult Balb/c mouse liver or EHBD by single cell RNA sequencing. Principal component analysis identified 6 major CD45+Linneg cell classes, two of which were restricted to the EHBD. One of these classes, biliary immature myeloid (BIM) cells, was predicted to interact with ILC2 by a network of shared receptor-ligand pairs. BIM highly expressed Gp49 and ST2 receptors on the cell surface while lacking surface expression of markers for mature myeloid cells. In conclusion, single cell RNA sequencing identified IL-33 responsive cell groups regionally confined to the liver or extrahepatic bile duct, including a novel population of CD45+Linneg Gp49-expressing mononuclear cells.

| S-EPMC6483339 | biostudies-literature

Cellular, transcriptomic and isoform heterogeneity of breast cancer cell line revealed by full-length single-cell RNA sequencing.

Project description:Tumor heterogeneity is generated through a combination of genetic and epigenetic mechanisms, the latter of which plays an important role in the generation of stem like cells responsible for tumor formation and metastasis. Although the development of single cell transcriptomic technologies holds promise to deconvolute this complexity, a number of these techniques have limitations including drop-out and uneven coverage, which challenge the further delineation of tumor heterogeneity. We adopted deep and full-length single-cell RNA sequencing on Fluidigm's Polaris platform to reveal the cellular, transcriptomic, and isoform heterogeneity of SUM149, a triple negative breast cancer (TNBC) cell line. We first validate the quality of the TNBC sequencing data with the sequencing data from erythroleukemia K562 cell line as control. We next scrutinized well-defined marker genes for cancer stem-like cell to identify different cell populations. We then profile the isoform expression data to investigate the heterogeneity of alternative splicing patterns. Though classified as triple-negative breast cancer, the SUM149 stem cells show heterogeneous expression of marker receptors (ER, PR, and HER2) across the cells. We identified three cell populations that express patterns of stemness: epithelial-mesenchymal transition (EMT) cancer stem cells (CSCs), mesenchymal-epithelial transition (MET) CSCs and Dual-EMT-MET CSCs. These cells also manifested a high level of heterogeneity in alternative splicing patterns. For example, CSCs have shown different expression patterns of the CD44v6 exon, as well as different levels of truncated EGFR transcripts, which may suggest different potentials for proliferation and invasion among cancer stem cells. Our study identified features of the landscape of previously underestimated cellular, transcriptomic, and isoform heterogeneity of cancer stem cells in triple-negative breast cancers.

| S-EPMC7114460 | biostudies-literature

Tissue-specific imprinting and heterogeneity of natural killer cells and group 1 innate lymphoid cells

Project description:We report here the identification, by CITE-seq and scRNA-seq, of distinct NK cells, ILC1s and intermediate subsets across 4 tissues at steady state. We found that unlike NK cells, which had a signature well conserved between organs, ILC1s exhibited a great heterogeneity depending on the tissue microenvironment, at both the phenotypic and transcriptomic levels. Finally, we performed a multidimensional comparison of these cells across tissues and identified sets of genes expressed by each related subsets.

2022-11-16 | GSE189807 | GEO

Human Innate Lymphoid Cell Subsets Possess Tissue-Type Based Heterogeneity in Phenotype and Frequency.

Project description:Animal models have highlighted the importance of innate lymphoid cells (ILCs) in multiple immune responses. However, technical limitations have hampered adequate characterization of ILCs in humans. Here, we used mass cytometry including a broad range of surface markers and transcription factors to accurately identify and profile ILCs across healthy and inflamed tissue types. High dimensional analysis allowed for clear phenotypic delineation of ILC2 and ILC3 subsets. We were not able to detect ILC1 cells in any of the tissues assessed, however, we identified intra-epithelial (ie)ILC1-like cells that represent a broader category of NK cells in mucosal and non-mucosal pathological tissues. In addition, we have revealed the expression of phenotypic molecules that have not been previously described for ILCs. Our analysis shows that human ILCs are highly heterogeneous cell types between individuals and tissues. It also provides a global, comprehensive, and detailed description of ILC heterogeneity in humans across patients and tissues.

| S-EPMC7612935 | biostudies-literature

Tissue residency of innate lymphoid cells in lymphoid and nonlymphoid organs.

Project description:Innate lymphoid cells (ILCs) contribute to barrier immunity, tissue homeostasis, and immune regulation at various anatomical sites throughout the body. How ILCs maintain their presence in lymphoid and peripheral tissues thus far has been unclear. We found that in the lymphoid and nonlymphoid organs of adult mice, ILCs are tissue-resident cells that were maintained and expanded locally under physiologic conditions, upon systemic perturbation of immune homeostasis and during acute helminth infection. However, at later time points after infection, cells from hematogenous sources helped to partially replenish the pool of resident ILCs. Thus, ILCs are maintained by self-renewal in broadly different microenvironments and physiological settings. Such an extreme "sedentary" lifestyle is consistent with the proposed roles of ILCs as sentinels and local keepers of tissue function.

| S-EPMC4720139 | biostudies-literature

Full-Length Isoform Sequencing Reveals Novel Transcripts and Substantial Transcriptional Overlaps in a Herpesvirus.

Project description:Whole transcriptome studies have become essential for understanding the complexity of genetic regulation. However, the conventionally applied short-read sequencing platforms cannot be used to reliably distinguish between many transcript isoforms. The Pacific Biosciences (PacBio) RS II platform is capable of reading long nucleic acid stretches in a single sequencing run. The pseudorabies virus (PRV) is an excellent system to study herpesvirus gene expression and potential interactions between the transcriptional units. In this work, non-amplified and amplified isoform sequencing protocols were used to characterize the poly(A+) fraction of the lytic transcriptome of PRV, with the aim of a complete transcriptional annotation of the viral genes. The analyses revealed a previously unrecognized complexity of the PRV transcriptome including the discovery of novel protein-coding and non-coding genes, novel mono- and polycistronic transcription units, as well as extensive transcriptional overlaps between neighboring and distal genes. This study identified non-coding transcripts overlapping all three replication origins of the PRV, which might play a role in the control of DNA synthesis. We additionally established the relative expression levels of gene products. Our investigations revealed that the whole PRV genome is utilized for transcription, including both DNA strands in all coding and intergenic regions. The genome-wide occurrence of transcript overlaps suggests a crosstalk between genes through a network formed by interacting transcriptional machineries with a potential function in the control of gene expression.

| S-EPMC5042381 | biostudies-literature

Transcriptional and Functional Programming of Decidual Innate Lymphoid Cells.

Project description:A successful pregnancy requires many physiological adaptations from the mother, including the establishment of tolerance toward the semiallogeneic fetus. Innate lymphoid cells (ILCs) have arisen as important players in immune regulation and tissue homeostasis at mucosal and barrier surfaces. Dimensionality reduction and transcriptomic analysis revealed the presence of two novel CD56Bright decidual ILCs that express low T-bet and divergent Eomes levels. Transcriptional correlation with recently identified first trimester decidual dNKs suggests that these novel decidual ILCs might be present throughout pregnancy. Functional testing with permutation analysis revealed production of multiple factors by individual cells, with a preference for IFNγ and VEGF. Overall, our data suggests continuity of a unique decidual innate lymphocytes across pregnancy with a polyfunctional functional profile conducive for pregnancy.

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