RNA-seq of CD4 CD8 lineage differentiation in the mouse thymus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA646978 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12252422_1.fastq.gz | Fastqsanger.gz | |||
| SRR12252422_2.fastq.gz | Fastqsanger.gz | |||
| SRR12252423_1.fastq.gz | Fastqsanger.gz | |||
| SRR12252423_2.fastq.gz | Fastqsanger.gz | |||
| SRR12252424_1.fastq.gz | Fastqsanger.gz |
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Project description:CD4 and CD8 identify helper and cytotoxic T cell lineages, and serve as co-receptors for MHC-restricted TCR recognition. Despite decades of investigation, questions remain about how TCR specificity and co-receptor gene expression are matched during T cell repertoire selection. Here we address the order and logic of CD4/CD8 lineage choice and differentiation by scRNA-seq. Maturation, activation, and lineage specification emerged as principle components, in this order. Co-receptor gene expression uncovered waves of Cd4+Cd8a+, Cd4+Cd8a- and Cd4-Cd8a+ selection intermediates and revealed gene expression programs associated with each pattern, including TCR- and cytokine signaling genes, lineage markers and transcription factors. While in the unperturbed thymus early Cd4+Cd8a+ selection intermediates were followed first by CD4-like Cd4+Cd8a- and later by CD8-like Cd4-Cd8a+ selection intermediates, the order of co-receptor gene expression was not inherently fixed. These data provide a benchmark for models of CD4/CD8 lineage choice, and a rich resource for interrogating T cell differentiation.
2020-10-25 | GSE149207 | GEO
Project description:scRNA-seq of mouse thymocyte CD4 CD8 lineage choice and differentiation
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Project description:The development of CD4+ T cells and CD8+ T cells in the thymus is critical to adaptive immunity and is widely studied as a model of lineage commitment. Recognition of self-MHCI or MHCII by the T cell antigen receptor (TCR) determines the CD8+ T cell or CD4+ T cell lineage choice, respectively, but how distinct TCR signals drive transcriptional programs of lineage commitment remains largely unknown. Here we applied CITE-seq to measure RNA and surface proteins in thymocytes from wild-type and T cell lineage-restricted mice to generate a comprehensive timeline of cell state for each T cell lineage. These analyses identified a sequential process whereby all thymocytes initiate CD4+ T cell lineage differentiation during an initial wave of TCR signaling, followed by a second TCR signaling wave that coincides with CD8+ T cell lineage specification. CITE-seq and pharmaceutical inhibition experiments implicated a TCR-calcineurin-NFAT-GATA3 axis in driving the CD4+ T cell fate. Our data provide a resource for understanding cell fate decisions and implicate multiple redundant mechanisms in guiding lineage choice.
2023-06-30 | GSE186078 | GEO
Project description:Conventional CD4 and CD8 single positive T cell lineages constitute the main differentiation pathway in the thymus. In human thymus, a minor TCRαβ differentiation pathway diverges from the early double positive stage, consisting of CD10+ PD-1+ cells. These cells are phenotypically and functionally similar to murine agonist-selected intraepithelial T lymphocyte precursors (IELps) which home to the small intestine. Here, the progeny of the human agonist-selected IEL lineage was identified in antigen-inexperienced cord blood (CB) with a polyclonal T cell receptor (TCR) repertoire exhibiting a bias towards early TCR alpha chain rearrangements and elevated autoreactive indices. Single-cell RNA sequencing allowed further delineation of this unconventional lineage in CB. Trajectory analysis, along with TCR repertoire analysis, transcriptomics and proteomics, suggests a precursor-progeny relationship with the thymic IELps. The distinct, heterogeneous CB population can now be defined as CD3+ TCRαβ+ CD4- CCR7- CD26-. Besides recent thymic emigrants, this population also consists of newly identified effector clusters and previously described populations: the suppressive NK receptor expressing CD8+ Treg population, the KIR/NKG2A+ EOMES+ virtual memory population and the CD8αα+ T cell populations. The population shows a discriminating stable HELIOS expression and is exclusively able to downregulate CD8β expression, resulting in double negative T cells. The functional properties of this population suggest that the cells expand on inflammatory cues and exert cytotoxic and proinflammatory activity.
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Project description:HDAC3 restrains CD8-lineage genes to maintain a bi-potential state in CD4+CD8+ thymocytes for CD4-lineage commitment
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Project description:In mice, contrary to conventional T cells, MAIT cells acquire a memory phenotype in the thymus in relation with Zbtb16 expression (Savage et al., 2008 ; Koay et al., 2016). To define phenotypic transcriptional signatures of MAIT subsets in the thymus, we analyzed by microarray the transcriptome of MAIT1 (MR1tet+RORgt+) and MAIT17 (MR1tet+RORgt+) as compared to conventional mature (TCRb+CD24lo) CD4+ and CD8+ single positive cells.
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Project description:During a binary cell fate decision, a progeny silences the gene expression program associated with the alternative fate. Helper versus cytotoxic lineage decision in the thymus has been studied as a model for gene silencing of alternative lineage genes, including Cd4. While RUNX3 is required for the initiation of Cd4 silencing, it remains unknown how silenced states of Cd4 and other helper lineage genes are maintained. We show that the histone methyltransferase G9a is necessary for heritable silencing of Cd4 and other helper lineage genes in CD8 T cells. Despite normal Cd4 downregulation during the development, G9a-deficient CD8 T cells fail to maintain silencing of helper lineage genes when they repeatedly divide under non-inflammatory conditions. However, Cd4 depression is prevented during division driven by elevated TCR signaling and an inflammatory cytokine signaling. These results reveal the requirement for G9a in silencing of helper lineage genes in CD8 T cells and also suggest that CD8 T cells employ an alternative mechanism to maintain their cellular identity during immune responses.
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Project description:Although BTB-zinc finger (BTB-ZF) transcription factors control the differentiation of multiple hematopoietic and immune lineages, how they function is poorly understood. The BTB-ZF factor Thpok controls intrathymic CD4+ T cell development and expression of most CD4+- and CD8+-lineage genes. Here, we identify the nucleosome remodeling and deacetylase (NuRD) complex as a novel Thpok cofactor. We locate three amino-acid residues within the Thpok BTB domain that are required for both NuRD binding and Thpok functions, and show that NuRD recruitment recapitulates the functions of the Thpok BTB domain. NuRD mediates Thpok repression of CD8+-lineage genes, including the transcription factor Runx3, but is dispensable for Cd4 expression. We show that these functions cannot be performed by the BTB domain of the Thpok-related factor Bcl6, which fails to bind NuRD. Thus, cofactor binding critically contributes to the functional specificity of BTB-zinc finger factors, which control the differentiation of most hematopoietic subsets.
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Project description:CD4 and CD8 mark helper and cytotoxic T cell lineages, respectively, and serve as coreceptors for MHC-restricted TCR recognition. How coreceptor expression is matched with TCR specificity is central to understanding CD4/CD8 lineage choice, but visualising coreceptor gene activity in individual selection intermediates has been technically challenging. It therefore remains unclear whether the sequence of coreceptor gene expression in selection intermediates follows a stereotypic pattern, or is responsive to signaling. Here we use single cell RNA sequencing (scRNA-seq) to classify mouse thymocyte selection intermediates by coreceptor gene expression. In the unperturbed thymus, Cd4+Cd8a- selection intermediates appear before Cd4-Cd8a+ selection intermediates, but the timing of these subsets is flexible according to the strength of TCR signals. Our data show that selection intermediates discriminate MHC class prior to the loss of coreceptor expression and suggest a model where signal strength informs the timing of coreceptor gene activity and ultimately CD4/CD8 lineage choice.
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Project description:Gene expression profiling has opened new directions of investigation in scientific research, however, the need for substantial amount of biological material to perform these experiments limits significantly its application range. Here, we have developed procedures to perform microarray analysis on amplified cDNA from single cells, including primary T lymphocytes, and applied this technology to the study of CD4 and CD8 lineage differentiation. Gene expression profiling was performed on samples of 1000 cells from 10 different subpopulations, defining the major stages of post-thymic CD4+ or CD8+ T-cell differentiation. Surprisingly, our data revealed that while CD4+ and CD8+ T-cells evolve differently at early stages of differentiation, they become increasingly similar as they reach late differentiation stages. This suggests that the functional heterogeneity of antigen experienced CD4+ and CD8+ T-cells is located early during post-thymic differentiation, and that late stages of differentiation may represent a common end in the development of T-lymphocytes. Keywords: Gene expression profiling
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