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Single-cell analysis of human MAIT cell transcriptional, functional and clonal diversity [Exp 2]

ABSTRACT: Mucosal-associated invariant T (MAIT) cells are innate-like T cells that recognize microbial metabolites through a semi-invariant T cell receptor (TCR). Major questions remain regarding the extent of human MAIT cell functional and clonal diversity. To address these, we analyzed the single-cell transcriptome and TCR repertoire of blood and liver MAIT cells and developed functional RNA sequencing, a method to integrate function and TCR clonotype at single-cell resolution. MAIT cell clonal diversity was comparable to conventional memory T cells, with private TCR repertoires shared across matched tissues. Baseline functional diversity was low and largely related to tissue site. MAIT cells showed stimulus-specific transcriptional responses in vitro, with cells positioned along gradients of activation. Clonal identity influenced resting and activated transcriptional profiles but intriguingly was not associated with the capacity to produce IL- 17. Overall, MAIT cells show phenotypic and functional diversity according to tissue localization, stimulation environment and clonotype.

ORGANISM(S): Homo sapiens

PROVIDER: GSE238137 | GEO | 2023/08/14

REPOSITORIES: GEO

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Single-cell analysis of human MAIT cell transcriptional, functional and clonal diversity [Exp 4]

Project description:Mucosal-associated invariant T (MAIT) cells are innate-like T cells that recognize microbial metabolites through a semi-invariant T cell receptor (TCR). Major questions remain regarding the extent of human MAIT cell functional and clonal diversity. To address these, we analyzed the single-cell transcriptome and TCR repertoire of blood and liver MAIT cells and developed functional RNA sequencing, a method to integrate function and TCR clonotype at single-cell resolution. MAIT cell clonal diversity was comparable to conventional memory T cells, with private TCR repertoires shared across matched tissues. Baseline functional diversity was low and largely related to tissue site. MAIT cells showed stimulus-specific transcriptional responses in vitro, with cells positioned along gradients of activation. Clonal identity influenced resting and activated transcriptional profiles but intriguingly was not associated with the capacity to produce IL- 17. Overall, MAIT cells show phenotypic and functional diversity according to tissue localization, stimulation environment and clonotype.

2023-08-14 | GSE238138 | GEO

Single-cell analysis of human MAIT cell transcriptional, functional and clonal diversity [Exp 1]

Project description:MAIT cells are innate-like T cells that recognize microbial metabolites through a semi-invariant T cell receptor (TCR). Major questions remain regarding the extent of human MAIT cell functional and clonal diversity. To address these, we analyzed the single-cell transcriptome and TCR repertoire of blood and liver MAIT cells and developed functional RNA-sequencing (fRNA-seq), a method to integrate function and TCR clonotype at single-cell resolution. MAIT cell clonal diversity was comparable to conventional memory T cells, with private TCR repertoires shared across matched tissues. Baseline functional diversity was low and largely related to tissue site. MAIT cells showed stimulus-specific transcriptional responses in vitro, with cells positioned along gradients of activation. Clonal identity influenced resting and activated transcriptional profiles, but intriguingly was not associated with the capacity to produce IL-17. Overall, MAIT cells show phenotypic and functional diversity according to tissue localization, stimulation environment, and clonotype.

2023-08-14 | GSE194187 | GEO

Single-cell analysis of human MAIT cell transcriptional, functional and clonal diversity [Exp 3]

2023-08-14 | GSE194188 | GEO

Single-cell analysis of human MAIT cell transcriptional, functional and clonal diversity [ATAC-seq]

2023-08-14 | GSE238139 | GEO

Parallel T-cell cloning and deep sequencing of the transcripts of human MAIT cells reveal stable oligoclonal TCRβ repertoire

Project description:Mucosal-associated invariant T (MAIT) cells are abundant in humans and recognize conserved bacterial antigens derived from riboflavin precursors, presented by the non-polymorphic MHC class I-like molecule MR1. Here, we show via transcriptomic analysis that human MAIT cells are remarkably oligoclonal in both blood and liver, display high inter-individual homology, and exhibit a restricted length CDR3β domain of the TCRVβ chain. We extend this analysis to a second sub-population of MAIT cells expressing a semi-invariant TCR conserved between individuals. Study of CDR3 regions of TCRalpha and beta sequences

2014-05-13 | E-GEOD-56055 | biostudies-arrayexpress

Mucosal-Associated Invariant T Cell Effector Function Is an Intrinsic Cell Property That Can Be Augmented by the Metabolic Cofactor α-Ketoglutarate

Project description:Mucosal-associated invariant T (MAIT) cells are an innate-like population of unconventional T cells that respond rapidly to vitamin B metabolite antigens or cytokine stimulation. Due to this reactivity and surface expression of CD45RO+, CD45RA−, CD127+, they are described as effector memory cells. Yet, there is a lack of uniformity in the MAIT cell effector response. it is unclear what factors contribute to setting MAIT cells effector capacity and whether it is fixed or can be modified. To address this, we have taken a systematic approach to examine MAIT cells effector capacity across healthy individuals in response to ligand and cytokine stimulation. We demonstrate the heterogenous nature of MAIT cells effector capacity, and that the ability to produce an effector response was not directly attributable to TCR clonotype or coreceptor expression. Global gene transcription analysis revealed that the MAIT cells effector capacity produced in response to TCR stimulation was associated with the expression of the epigenetic regulator lysine demethylase 6B (KDM6B). Addition of a KDM6B inhibitor does not alter MAIT cell effector function. However, addition of the KDM6B cofactor α-ketoglutarate greatly enhanced MAIT cells effector capacity in a KDM6B-dependent manner. These results demonstrate that the MAIT cells effector response is epigenetically regulated and can be targeted for enhancement.

2021-01-14 | GSE164740 | GEO

Human MAIT cells exit peripheral tissues and re-circulate via lymph in steady state conditions

Project description:Mucosal-associated invariant T (MAIT) cells recognize bacterial metabolites as antigen and are found in blood and tissues, where they are poised to contribute to barrier immunity. Recent data demonstrate that MAIT cells located in mucosal barrier tissues are functionally distinct from their blood counterparts, but the relationship and circulation of MAIT cells between blood and different tissue compartments remains poorly understood. Previous studies raised the possibility that MAIT cells do not leave tissue and may either be retained or undergo apoptosis. To directly address if human MAIT cells exit tissues, we collected human donor-matched thoracic duct lymph and blood and analyzed MAIT cell phenotype, transcriptome and TCR diversity by RNAseq.

2018-03-26 | GSE106288 | GEO

Single cell transcriptional profiling reveals signatures of helper, effector, and regulatory MAIT cells during homeostasis and activation

Project description:Mucosal-associated invariant T (MAIT) cells are innate-like lymphocytes that recognize microbial vitamin B metabolites and have emerging roles in infectious disease, autoimmunity, and cancer. Although MAIT cells are identified by a semi-invariant T cell receptor, their phenotypic and functional heterogeneity is not well understood. Here we present an integrated single cell transcriptomic analysis of over 76,000 human MAIT cells during acute and chronic antigen-specific activation with the MR1 ligand 5-OP-RU and non-specific TCR stimulation. We show that MAIT cells span a broad range of homeostatic, effector, helper, tissue-infiltrating, regulatory, and exhausted phenotypes, with distinct gene expression programs associated with CD4+ or CD8+ co-expression. During acute activation, MAIT cells rapidly adopt a cytotoxic phenotype characterized by high expression of GZMB, IFNG and TNF. In contrast, chronic stimulation induces heterogeneous states defined by proliferation, cytotoxicity, immune modulation, and exhaustion. We further demonstrate a FOXP3 expressing MAIT cell subset that phenotypically resembles conventional regulatory T cells. Moreover, scRNAseq-defined MAIT cell subpopulations were also detected in individuals recently exposed to Mycobacterium tuberculosis, confirming their presence during human infection. Our study provides the first comprehensive atlas of human MAIT cells in activation conditions and defines substantial functional heterogeneity, suggesting complex roles in health and disease.

2021-08-19 | GSE182239 | GEO

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

Peripheral blood TCR clonotype diversity as an age-associated marker of breast cancer progression (blood)

Project description:Immune escape is a prerequisite of tumor growth. We previously described a decline in intratumor activated GZMB+CD8+ T cells and T cell receptor (TCR) clonotype diversity in invasive compared to in situ (DCIS) breast carcinomas implying a role for decreasing TCR diversity in tumor progression. Here, we evaluated peripheral blood TCR clonotype diversity in breast cancer patients diagnosed with DCIS or de novo stage IV disease at different ages. We found that peripheral TCR diversity is associated with clinicopathologic, and peripheral immune status and it correlates with the frequency of CD8+ T cells in DCIS of young patients. These results provide new insights to the role of host immunity and breast cancer development in different aged women.

2023-11-09 | GSE239933 | GEO

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