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

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

PROVIDER: PRJNA506214 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8209460_1.fastq.gz	Fastqsanger.gz
	SRR8209460_2.fastq.gz	Fastqsanger.gz
	SRR8209470_1.fastq.gz	Fastqsanger.gz
	SRR8209470_2.fastq.gz	Fastqsanger.gz
	SRR8209461_1.fastq.gz	Fastqsanger.gz

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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

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

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

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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.

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Project description:Mesenteric lymph node (mLN) T cells undergo tissue adaptation upon migrating to intestinal lamina propria (LP) and intraepithelial (IE) compartments, ensuring appropriate balance between tolerance and resistance. By combining mouse genetics with single-cell and chromatin analyses, we addressed the molecular imprinting of gut epithelium on T cells. Transcriptionally, conventional and regulatory (Treg) CD4+ T cells from mLN, LP and IE segregate based on the gut layer they occupy; trajectory analysis suggests a stepwise loss of CD4-programming and acquisition of an intraepithelial profile. Treg fate–mapping coupled with RNA– and ATAC–sequencing revealed that the Treg program shuts down before an intraepithelial program becomes fully accessible at the epithelium. Ablation of CD4 lineage–defining transcription factor ThPOK results in premature acquisition of an IEL profile by mLN Tregs, partially recapitulating epithelium imprinting. Thus, coordinated replacement of circulating lymphocyte program with site–specific transcriptional and chromatin changes is necessary for tissue imprinting.

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Stepwise chromatin and transcriptional acquisition of an intraepithelial lymphocyte program

Project description:Stepwise chromatin and transcriptional acquisition of an intraepithelial lymphocyte program

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Project description:The thymus is the site of T lymphocyte development and T cell education to recognize foreign, but not self, antigens. B cells also reside and develop in the thymus, although their function(s) are less clear. During ‘thymic involution,’ a process of lymphoid atrophy and adipose replacement linked to sexual maturation, thymic cells decline. However, thymic B cells decrease far less than T cells, such that B cells comprise ~1% of neonatal thymocytes, but up to ~10% in adulthood in humans. All jawed vertebrates possess a thymus, and we and others have shown that zebrafish (Danio rerio) also have thymic B cells. Here, we investigated the precise identities of zebrafish thymic T and B cells and how they change with involution. We assessed the timing and specific details of zebrafish thymic involution using multiple lymphocyte-specific, fluorophore-labeled transgenic lines, quantifying changes in thymic lymphocytes pre- vs. post-involution. Our results prove that, as in humans, zebrafish thymic B cells increase relative to T cells post-involution. We also performed RNA sequencing (RNA-seq) on D. rerio thymic and marrow lymphocytes of four novel double-transgenic lines, identifying distinct populations of immature T and B cells. Collectively, this is the first comprehensive analysis of zebrafish thymic involution, demonstrating its similarity to human involution, and establishing the highly genetically-manipulatable zebrafish model as a template for involution studies.

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Elevated T cell receptor signaling identifies a thymic precursor to the TCR??(+)CD4(-)CD8?(-) intraepithelial lymphocyte lineage.

Project description:The origin and developmental pathway of intestinal T cell receptor ??(+) CD4(-)CD8?(-) intraepithelial lymphocytes (unconventional iIELs), a major population of innate-like resident cytolytic T cells, have remained elusive. By cloning and expressing several TCRs isolated from unconventional iIELs, we identified immature CD4(lo)CD8(lo)(DP(lo))CD69(hi)PD-1(hi) thymocytes as the earliest postsignaling precursors for these cells. Although these precursors displayed multiple signs of elevated TCR signaling, a sizeable fraction of them escaped deletion to selectively engage in unconventional iIEL differentiation. Conversely, TCRs cloned from DP(lo)CD69(hi)PD-1(hi) thymocytes, a population enriched in autoreactive thymocytes, selectively gave rise to unconventional iIELs upon transgenic expression. Thus, the unconventional iIEL precursor overlaps with the DP(lo) population undergoing negative selection, indicating that, concomitant with the downregulation of both CD4 and CD8 coreceptors, a balance between apoptosis and survival signals results in outcomes as divergent as clonal deletion and differentiation to the unconventional iIEL lineage.

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Transcription factor T-bet regulates intraepithelial lymphocyte functional maturation.

Project description:The intestinal epithelium harbors large populations of activated and memory lymphocytes, yet these cells do not cause tissue damage in the steady state. We investigated how intestinal T cell effector differentiation is regulated upon migration to the intestinal epithelium. Using gene loss- and gain-of-function strategies, as well as reporter approaches, we showed that cooperation between the transcription factors T-bet and Runx3 resulted in suppression of conventional CD4(+) T helper functions and induction of an intraepithelial lymphocyte (IEL) program that included expression of IEL markers such as CD8?? homodimers. Interferon-? sensing and T-bet expression by CD4(+) T cells were both required for this program, which was distinct from conventional T helper differentiation but shared by other IEL populations, including TCR??(+)CD8??(+) IELs. We conclude that the gut environment provides cues for IEL maturation through the interplay between T-bet and Runx3, allowing tissue-specific adaptation of mature T lymphocytes.

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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.

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Project description:Murine gamma delta intraepithelial lymphocyte response to type I IFN and TCR blockade

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