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Distinct metabolic programmes established in the thymus control the effector functions of γδ T cell subsets in tumour microenvironments

ABSTRACT: Distinct metabolic programmes established in the thymus control the effector functions of γδ T cell subsets in tumour microenvironments

PROVIDER: PRJNA659017 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12508462.fastq.gz	Fastqsanger.gz
	SRR12508462_1.fastq.gz	Fastqsanger.gz
	SRR12508462_2.fastq.gz	Fastqsanger.gz
	SRR12508463.fastq.gz	Fastqsanger.gz
	SRR12508463_1.fastq.gz	Fastqsanger.gz

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Distinct metabolic programmes established in the thymus control the effector functions of γδ T cell subsets in tumour microenvironments

Project description:RNA sequencing of PLZF+ and PLZF- γδ T cell subsets from the spleen, inguinal lymph nodes, lungs and adipose tissue for gene expression analysis

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The human fetal thymus generates effector invariant γδ T cells in a Lin28b-dependent manner

Project description:In the mouse thymus, invariant γδ T cells are generated at well-defined times during development and acquire effector functions before exiting the thymus. However, whether such thymic programming can occur in human is not known. Here we analyzed human fetal and post-natal γδ thymocytes and investigated the role of hematopoietic-stem-and-precursor-cells (HSPC) in the generation of human γδ T cells. Unlike post-natal γδ thymocytes, fetal γδ thymocytes were functionally programmed (e.g. IFNγ, granzymes), expressed low levels of terminal-deoxynucleotidyl-transferase (TdT) and were highly enriched for invariant/public germline-encoded CDR3 sequences (TRGV8-TRJP1-CATWDTTGWFKIF, TRDV2-TRDD3-CACDTGGY and TRDV1-TRDD3-CALGELGD, previously shown to be expanded in cytomegalovirus infection) composed of short-homology-repeat-containing gene segments. Furthermore, these unique characteristics were due to an intrinsic property of fetal HSPC caused by high expression of the RNA-binding protein Lin28b. In conclusion, our data indicate that the human fetal thymus generates, in a HSPC/Lin28b-dependent manner, invariant γδ T cells with programmed effector functions.

2019-11-21 | GSE128163 | GEO

MHC class II inhibits the generation of IL-17A+ Vγ6 γδ T cells in the thymus at perinatal stage

Project description:TCR γ chain loci of mice have seven variable (Vγ) gene segments (Vγ1, Vγ2, Vγ3, Vγ4, Vγ5, Vγ6, and Vγ7) using the Heilig and Tonegawa nomenclature. Vγ6+ γδ T cells, which develop in the thymus at the perinatal stage, are distributed within the mucosal tissues in the periphery. Vγ6+ γδ T cells are exclusive interleukin (IL)-17 producers among γδ T cells, and Vγ6+ IL-17A+ γδ T (γδT17) cells play important roles in protection against microbial infection and in the pathogenesis of inflammatory diseases, such as colitis and autoimmune diseases. We have previously reported that γδT17 cells develop from the CD4–CD8– (DN)2b stage in the thymus at the prenatal stage in a Bcl11b-dependent manner. However, details of the development of Vγ6+ γδT17 cells remain obscure. To analyze Vγ6+ γδ T cells in detail, we recently developed a monoclonal antibody (mAb; termed 1C10-1F7) specific to mouse Vg6 chain. Use of this mAb revealed that Vγ6+ γδ T cells in 0-day-old thymus were co-localized with medullary thymic epithelial cells (mTECs), which regulate T cell tolerance by self-antigen presentation using major histocompatibility complex (MHC) class II. Here, we report that MHC class II in the thymus inhibits the generation of Vγ6+ γδT17 cells.

2022-08-01 | GSE180320 | GEO

Distinct metabolic programs established in the thymus control effector functions of γδ T cell subsets in tumor microenvironments.

Project description:Metabolic programming controls immune cell lineages and functions, but little is known about γδ T cell metabolism. Here, we found that γδ T cell subsets making either interferon-γ (IFN-γ) or interleukin (IL)-17 have intrinsically distinct metabolic requirements. Whereas IFN-γ+ γδ T cells were almost exclusively dependent on glycolysis, IL-17+ γδ T cells strongly engaged oxidative metabolism, with increased mitochondrial mass and activity. These distinct metabolic signatures were surprisingly imprinted early during thymic development and were stably maintained in the periphery and within tumors. Moreover, pro-tumoral IL-17+ γδ T cells selectively showed high lipid uptake and intracellular lipid storage and were expanded in obesity and in tumors of obese mice. Conversely, glucose supplementation enhanced the antitumor functions of IFN-γ+ γδ T cells and reduced tumor growth upon adoptive transfer. These findings have important implications for the differentiation of effector γδ T cells and their manipulation in cancer immunotherapy.

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Project description:Recent advances in next-generation sequencing technologies elucidated gene regulatory networks and TCR signaling molecules underlying functional differentiation into γδ1 and γδ17 cells that now provide valid resources to define developing CD24+ γδ, γδ1 and γδ17 cells. The γδ1 cell subsets express key transcription factors of cytotoxicity and IFNγ-production, such as Tbx21 (encoding T-bet) and Eomes, as well as natural killer receptor (NKRs). Development of γδ17 cells is favorable in the early life period, regulated by Notch signaling and a network of transcriptional regulators including cMaf, Sox13, Blk, and Rorc that are essential for functional differentiation. However, detailed knowledge about molecular programs of Vγ4 cells, including their potential to become γδ1 or γδ17 cells during adult thymus development, is lacking. Here we employed transcriptional and epigenetic analysis of Vγ4 cells under steady-state conditions and after induction of de novo T cell development from adult thymus precursor cells.

2023-01-13 | GSE222588 | GEO

SLAM/SAP signaling regulates discrete γδ T cell developmental checkpoints and shapes the innate-like γδ TCR repertoire

Project description:During thymic development, most γδ T cells acquire innate-like characteristics that are critical for their function in tumor surveillance, infectious disease, and tissue repair. The mechanisms, however, that regulate γδ T cell developmental programming remain unclear. Recently, we demonstrated that the SLAM-SAP signaling pathway regulates the development and function of multiple innate-like γδ T cell subsets. Here, we used a single-cell proteogenomics approach to identify SAP-dependent developmental checkpoints and to define the SAP-dependent γδ TCR repertoire. SAP deficiency resulted in both a significant loss of an immatureGzma+Blk+Etv5+Tox2+γδT17 precursor population, and a significant increase inCd4+Cd8+Rorc+Ptcra+Rag1+thymic γδ T cells. SAP-dependent diversion of embryonic day 17 thymic γδ T cell clonotypes into the αβ T cell developmental pathway was associated with a decreased frequency of mature clonotypes in neonatal thymus, and an altered γδ TCR repertoire in the periphery. Finally, we identify TRGV4/TRAV13-4(DV7)-expressing T cells as a novel, SAP-dependent Vγ4 γδT1 subset. Together, the data suggest that SAP-dependent γδ/αβ T cell lineage commitment regulates γδ T cell developmental programming and shapes the γδ TCR repertoire.

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Single cell RNAseq of gammadelta T cells from murine thymus and liver

Project description:Until now, the systematic and comprehensive deciphering of γδ T heterogeneity and the extrathymic developmental pathway of liver γδ T cells remains largely unsolved. In this study, we performed single cell RNA sequencing to comprehensively identify the heterogeneity of γδ T cells from murine liver and thymus. We further revealed the developmental trajectory of γδ T cells and found that liver contains γδ T precursors.

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Expression data from mouse small intestinal γδ intraepithelial lymphocytes

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Epigenetic profiling reveals developmental traits of adult thymus-derived Vγ4+ γδ T cells

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