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Transcriptomes and metabolism define heterogeneous mouse and human MAIT cells [mouse]

ABSTRACT: Mucosal-associated invariant T (MAIT) cells are a subpopulation of T lymphocytes that respond to microbial metabolites. We performed single-cell RNA sequencing and metabolic analyses in MAIT cell subsets in thymus and peripheral tissues from mice and humans to define the heterogeneity and developmental path of these innate-like lymphocytes. We show that the predominant mouse subset, which produces IL-17 (MAIT17), and the subset that produces IFN (MAIT1), have greatly different transcriptomes and metabolic states in the thymus and periphery. A subset has a transcriptome similar to circulating lymphocytes, and in mice these are found in recent thymic emigrants, suggesting partially mature cells emigrate from the thymus. Human MAIT cells are predominantly MAIT1 cells, but have a different metabolism from naïve CD8 T cells with increased fatty acid uptake and storage. Although mouse and human subsets are similar in thymus, in the periphery they are divergent, likely reflecting environmental and genetic differences.

ORGANISM(S): Mus musculus

PROVIDER: GSE189484 | GEO | 2023/11/13

REPOSITORIES: GEO

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Transcriptomes and metabolism define heterogeneous mouse and human MAIT cells [human]

Project description:Mucosal-associated invariant T (MAIT) cells are a subpopulation of T lymphocytes that respond to microbial metabolites. We performed single-cell RNA sequencing and metabolic analyses in MAIT cell subsets in thymus and peripheral tissues from mice and humans to define the heterogeneity and developmental path of these innate-like lymphocytes. We show that the predominant mouse subset, which produces IL-17 (MAIT17), and the subset that produces IFN (MAIT1), have greatly different transcriptomes and metabolic states in the thymus and periphery. A subset has a transcriptome similar to circulating lymphocytes, and in mice these are found in recent thymic emigrants, suggesting partially mature cells emigrate from the thymus. Human MAIT cells are predominantly MAIT1 cells, but have a different metabolism from naïve CD8 T cells with increased fatty acid uptake and storage. Although mouse and human subsets are similar in thymus, in the periphery they are divergent, likely reflecting environmental and genetic differences.

2023-11-13 | GSE189483 | GEO

Microarray expression profiling of MAIT subsets isolated from thymus of B6-MAIT/CAST mice, as compared to single positive CD4 or CD8 conventional T cells.

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.

2019-07-01 | E-MTAB-7702 | biostudies-arrayexpress

Innate-like T cell subset commitment in the murine thymus is independent of TCR characteristics and occurs during proliferation

Project description:we compare the TCR repertoires of MAIT1 and MAIT17 cells from the mouse thymus using 5’ scRNAseq and scTCRseq of MR1:5-OP-RU tetramer positive thymocytes. A thorough analysis of TCR features between MAIT sub-populations did not show any difference between the repertoires of MAIT1 and MAIT17 subsets. Quantitative simulation of clonotype distributions of MAIT1 and MAIT17 cells allowed us to investigate the role of TCR characteristics in MAIT fate choice, and to pinpoint the stage at which lineage commitment occurs. Our results indicate that the TCR characteristics are not instructive in MAIT lineage choice and that MAIT1/17 commitment takes place during MAIT cell proliferation in the thymus. Finally, we performed analogous analysis of a published scRNA-seq and scTCR-seq dataset of iNKT from mouse thymus and demonstrated that our conclusions are also relevant for iNKT1 vs iNKT17 fate commitment.

2024-04-10 | GSE236666 | GEO

Role of AhR in thymocyte emigration in vivo

Project description:Over-activation of the aryl hydrocarbon receptor by TCDD in mice leads among other phenotypes to a severe thymic atrophy accompanied by immunosuppression. TCDD causes a block in thymocyte maturation and a preferential emigration of immature CD4-CD8- DN thymocytes (recent thymic emigrants) into the periphery. As part of this study gene expression profiles from DN thymocytes and thymic emigrants were generated from TCDD and solvent control mice Keywords: Affymetrix, TCDD, CD4-CD8- thymocytes, Thymus involution, thymic emigration, Ahr Female, 6-8 week old C57BL6 mice were i.p. injected with 10 M-BM-5g/kg TCDD. After 5 days mice were anesthezised and FITC injected into their thymi. after 24h mice were sacrificed and CD4-CD8-FITC+ cells isolated from thymus (thymocytes) and spleen (recent thymus emigrants).

2008-11-25 | E-GEOD-10166 | biostudies-arrayexpress

Single cell RNA-seq of metabolite specific T-cells (MR1-restricted) from adult mouse thymus

Project description:Mucosal-Associated Invariant T cells (MAIT cells) have a unique specificity for the microbial metabolite 5-OP-RU presented by the non-classical presentation molecule MR1. Upon activation, they release cytotoxic mediators and engage an antimicrobial activity. As a subset of T lymphocytes, MAIT development occurs in the thymus where they acquire their effector phenotype under the control of the key transcription factor ZBTB16. This particular maturation process is in contrast with conventional T cells that egress the thymus with a naive phenotype before populating the secondary lymphoid organs, and the molecular events driving the MAIT lineage decision are poorly known. In the present work, we evaluated the transcriptional events and the role of the slam-SAP pathway on the lineage decision of MR1-restricted T cells by single cell RNAseq. MAIT cells undergoing positive selection were FACS-sorted with a MR1:5-OP-RU labeled tetramer, from thymus of wild-type and sapKO mice. Their transcriptomes were captured using a 10x chromium system.

2019-07-01 | E-MTAB-7704 | biostudies-arrayexpress

RNA-seq expression profiling of humain MAIT cells in blood and liver as compared to mainstream TCD4+ and TCD8+ cells.

Project description:At variance with what is observed in mice, no distinct MAIT1 or MAIT17 subsets exist in human blood, as all MAIT cells express a variety of transcription factors such as Rorgt, Tbet, Eomes and Helios. However, they are also found in tissues in which they have specific effector functions. To determine these tissue programs, we analyzed the transcription pattern of MAIT cells as compared to mainstream memory (CD45RA-CD27+) CD4+ and CD8+ T cells from human blood and liver. The paired samples of blood and liver cells were obtained from patients operated for metastatic uveal melanoma (liver samples from a “healthy” liver fragment), and from the blood of healthy controls.

2018-12-03 | E-MTAB-7143 | biostudies-arrayexpress

Mucosal-associated invariant T cells contribute to suppression of inflammatory myeloid cells in immune-mediated kidney disease

Project description:Mucosal-associated invariant T (MAIT) cells have been implicated in various inflammatory diseases of barrier organs, but so far, their role in kidney disease is unclear. Here we report that MAIT cells that recognize their prototypical ligand, the vitamin B2 intermediate 5-OP-RU presented by MR1, reside in human and mouse kidneys. Single cell RNAseq analysis reveals several intrarenal MAIT subsets, and one, carrying the genetic fingerprint of tissue-resident MAIT17 cells, is activated and expanded in a murine model of crescentic glomerulonephritis (cGN). An equivalent subset is also present in kidney biopsies of patients with anti-neutrophil cytoplasmatic antibody (ANCA)-associated cGN. MAIT cell-deficient MR1 mice show aggravated disease, whereas B6-MAITCAST mice, harboring higher MAIT cell numbers, are protected from cGN. The expanded MAIT17 cells express anti-inflammatory mediators known to suppress cGN, such as CTLA-4, PD-1, and TGF-β. Interactome analysis predicts CXCR6 – CXCL16-mediated cross-talk with renal mononuclear phagocytes, known to drive cGN progression. In line, we find that cGN is aggravated upon CXCL16 blockade. Finally, we present an optimized 5-OP-RU synthesis method which we apply to attenuating cGN in mice. In summary, we propose that CXCR6+ MAIT cells might play a protective role in cGN, implicating them as a potential target for anti-inflammatory therapies.

2023-10-13 | GSE245302 | GEO

Role of AhR in thymocyte emigration in vivo

2008-11-25 | GSE10166 | GEO

Role of splicing factor SRSF1 during the late stages of T cell maturation in the thymus

Project description:In thymus, the post-selection single positive thymocytes undergo further intrathymic maturation including down-regulation of CD69 and CD24, up-regulation of Qa-2, through which single positive thymocytes became equipped with emigration competency, then emigrate to periphery. Here we find that RNA binding protein Srsf1 is essential for the final maturation and survival of thymocytes.

2021-04-21 | GSE141349 | GEO

Microarray expression profiling of NKT and MAIT subsets in different organs of B6-MAIT/CAST mice.

Project description:MAIT cells (MAITs) represent an abundant T lymphocyte subset with unique specificity for microbial metabolites presented by the MHC-1b molecule, MR1. MAIT conservation along evolution indicates important, non-redundant functions, but their low frequency in mice has hampered their detailed characterization. Here, we performed a transcriptomic analysis of murine MAITs in comparison with NKT subsets and with mainstream T cells in spleen and peripheral organs of B6-MAIT/CAST mice expressing a Rorc-GFP transgene. MAIT and NKT cells have been FACS-sorted after tetramer staining (MR1:5-OP-RU Tet+ for MAIT, CD1d:PBS57Tet+ for NKT), and 1/17 subsetting based on the expression of Rorc.

2018-12-03 | E-MTAB-7133 | biostudies-arrayexpress

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