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Single-cell transcriptional profiling identifies a spectrum of unconventional intraepithelial T lineage cells in human cord blood [TCR sequencing]

ABSTRACT: 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 and transcriptomics, 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE201810 | GEO | 2023/03/07

REPOSITORIES: GEO

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Single-cell transcriptional profiling identifies a spectrum of unconventional intraepithelial T lineage cells in human cord blood

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.

2023-02-10 | PXD033392 | Pride

Single-cell transcriptional profiling identifies a spectrum of unconventional intraepithelial T lineage cells in human cord blood [scRNA-Seq]

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 and transcriptomics, 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.

2023-03-07 | GSE201809 | GEO

Single-cell transcriptional profiling identifies a spectrum of unconventional intraepithelial T lineage cells in human cord blood [bulk RNA-Seq]

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 and transcriptomics, 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.

2023-03-07 | GSE201808 | GEO

BCL6 is required for the thymic development of TCRαβ+CD8αα+ intraepithelial lymphocyte lineage

Project description:TCRαβ+CD8αα+ intraepithelial lymphocytes (CD8αα+ αβ IELs), a specialized subset of T cells in the gut epithelium, develop from thymic agonist-selected IEL precursors (IELps). The molecular mechanisms underlying the selection and differentiation of this T cell type in the thymus are largely unknown. Here, we found that Bcl6 deficiency in αβ T cells resulted in nearly the absence of CD8αα+ αβ IELs. BCL6 was expressed by approximately 50% of CD8αα+ αβ IELs but the majority thymic PD1+ IELps post agonist selection; its deficiency blocked early IELp generation in the thymus. Moreover, BCL6 expression in IELps was induced by thymic TCR signaling in an ERK-dependent manner. As a result of Bcl6 deficiency, the precursors of IELps among CD4+CD8+ double positive (DP) thymocytes exhibited increased apoptosis during agonist selection, and impaired IELp differentiation and maturation. Taken together, our results elucidate BCL6 as a crucial transcription factor during the thymic development of CD8αα+ αβ IELs.

2024-02-26 | GSE248163 | GEO

Single cell RNA sequencing identifies the developmental origin of C-Myc dependent T-bet+thymic intraepithelial lymphocyte precursor

Project description:Natural intraepithelial lymphocytes (IELs) are thymus-derived adaptive immune cells, which are important contributors to intestinal immune homeostasis. Similar to other innate-like T cells they are induced in the thymus through high-avidity interaction that would otherwise lead to clonal deletion in conventional CD4 and CD8 T cells. By applying single-cell RNA-sequencing (scRNA-seq) on a heterogeneous population of IEL precursors (IELPs) we define a developmental trajectory that identifies Id3 as a novel regulator of IELP development and shows that all natural TCRαβ+ IELPs progress through a PD-1 stage as a result of strong agonist selection. Furthermore, with the use of newly developed PD-1 fate map and conditional T-bet knockout mice we demonstrate that this PD-1 stage precedes the induction of T-bet. The transition from PD-1 to T-bet is regulated by the transcription factor C-Myc, as T cell-specific conditional C-myc knockout mice lack PD-1-T-bet+ IELPs, while PD-1+T-bet- IELPs are still present. In summary, our results provide a high-resolution molecular framework for thymic IEL development and deepen our understanding of this still elusive cell type.

2019-11-20 | GSE122740 | GEO

The thymoproteasome hardwires the TCR repertoire of CD8+ T cells in the cortex independent of negative selection

Project description:The thymoproteasome expressed specifically in thymic cortical epithelium optimizes the generation of CD8+ T cells. However, how the thymoproteasome contributes to CD8+ T cell development is unclear. Here we show that the thymoproteasome shapes the TCR repertoire directly in cortical thymocytes before migration to the thymic medulla. We further show that the thymoproteasome optimizes CD8+ T cell production independent of the thymic medulla, independent of additional antigen-presenting cells including medullary thymic epithelial cells and dendritic cells, and independent of apoptosis-mediated negative selection. These results indicate that the thymoproteasome hardwires the TCR repertoire of CD8+ T cells with cortical positive selection independent of negative selection in the thymus.

2021-02-01 | GSE164895 | GEO

Notch signaling is required for induction of an innate T cell development program in human thymus

Project description:CD4 CD8 double positive (DP) thymocytes progressively shut down Notch signaling after β-selection allowing progression of the DP program and positive selection of conventional CD4 and CD8 single positive T cells. In contrast, innate CD8+ T cells are selected from DP precursors shortly after β-selection. Here, we investigated whether notch signaling is required for the initiation of the innate T cell developmental program upon TCR engagement. We show that, after β-selection, Notch activation limits progression to late DP cells and favors the development of TCRαβ/CD3 expressing CD8dim early DP progenitors. TCR engagement in these Notch dependent TCRαβ+ early DP precursors does not induce prominent apoptosis, but rather induces T-bet expression by an mTOR-dependent mechanism. Our findings indicate that Notch signaling drives the launch of an innate effector program in response to TCR agonist selection in the thymus.

2019-09-05 | GSE100519 | GEO

BCR repertoire analyis of class-switched and non-switched thymic B cells

Project description:We report that a large percentage of thymic B cells undergo class switching intrathymically. Thymic B cell class switching requires cognate T-B interaction. To determine whether B cell specificity was also important for thymic B cell class-switching, we sorted class-switched thymic B cells (CD19+B220+IgM-IgD-), unswitched B cells (CD19+B220+IgM+IgD+) and bulk splenic B cells in 3H9 heavy chain-fixed mice and performed high throughput sequencing analysis of the light chain of these populations. Results of this analysis indicated that class-switched thymic B cells have a distinct repertoire compared with unswitched thymic B cells and splenic B cells. Further reactivity tests indicated that a large part of BCRs enriched in class-switched thymic B cells are autoreactive. These data suggest that autoreactive B cells are selected into class-switched population and expanded in the thymus. Light chain repertoire profiles of class-switched thymic B cells, unswithced thymic B cells and splenic B cells from 3H9 mice were generated by deep sequencing.

2016-08-10 | E-GEOD-85366 | biostudies-arrayexpress

Analysis of transcriptomic profile of iNKT cells

Project description:The maintenance of tissue homeostasis is critically dependent on the function of tissue-resident lymphocytes, including lipid-reactive invariant natural killer T (iNKT) cells. iNKT cells have unique properties according to their tissues of residency, but if and how the tissue environment shapes their antigen specificity remains unknown. By analysing iNKT cells from tissues of mice and humans we demonstrate that their T cell receptor (TCR) repertoire is highly diverse and is distinct for iNKT cells resident in individual tissues resulting in differential lipid-antigen recognition. Within peripheral tissues, the TCR repertoire of iNKT cell recent thymic emigrants is different from that of mature cells, indicating that the iNKT population is shaped after their arrival to the tissues. Accordingly, in homeostatic conditions the repertoire of iNKT cells is modulated by tissue-specific signals that control iNKT cell activation and proliferation resulting in differential clonal expansion found for cells resident in various organs. Moreover, the iNKT cell TCR repertoire changes in response to lipid immunization and is shaped by age and by environmental changes. Thus, post-thymic modification of the iNKT cell TCR repertoire underpins the distinct antigen specificity of iNKT cells residing in peripheral tissues

2019-12-17 | GSE131420 | GEO

Generation of mature T cells from human hematopoietic stem/progenitor cells in artificial thymic organoids

Project description:Mechanistic studies of human T cell development require robust model systems that recapitulate the full span of thymopoiesis, from hematopoietic stem and progenitor cells (HSPC) through to mature naïve T cells. We developed a serum free, artificial thymic organoid (ATO) system that supports highly efficient and reproducible in vitro differentiation and positive selection to generate conventional human T cells from all sources of HSPCs. Deep-sequencing of the TCR variable genes was performed to compare the diversity of the TCR repertoire between ATO-derived CD8SP T cells and naive CD8SP T cells from thymus and blood.

2017-02-17 | GSE94968 | GEO

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