Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Human MAIT10 and MAIT17 profiles are effector states directed by the cytokine milieu

ABSTRACT: Mucosa-associated invariant T (MAIT) cells are unconventional MR1-restricted T cells with rapid innate-like response characteristics. MAIT cells can mediate broad effector functions, including bacterial cytolysis and production of a range of pro-inflammatory cytokines. However, how the MAIT cell antigen response profile is controlled is unclear. Incorporating functional and transcriptomic analyses we define three distinct MAIT cell effector programs driven by the cytokine milieu during antigen recognition. Activation by TCR signaling together with IL-12 or IL-23 drives a program biased towards IL-10 through the transcription factor c-MAF and the expression of the inhibitory receptors TIM-3, LAG-3 and PD-1 (MAIT10). Co-activation with IL-18 supports responses dominated by IL-17, GM-CSF, IFNγ and TNF (MAIT17). The IL-18-driven inflammatory and tissue-repair program vetoes IL-10 expression. On the contrary, TCR activation without cytokine co-activation drives primarily cytolytic arming. These activation states are transient and reflect the adaptation of MAIT cells to the local milieu. MAIT cell IL-10 production serves an autocrine regulatory function in addition to influence the state of monocytes. Finally, in active Crohn’s disease patients, the MAIT10 profile is suppressed. Together, these findings demonstrate that MAIT cells adapt their effector response programs to the local cytokine milieu.

ORGANISM(S): Homo sapiens

PROVIDER: GSE241077 | GEO | 2025/01/19

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

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

Inflammatory Cytokines Induce Sustained CTLA-4 Cell Surface Expression on Human MAIT Cells

Project description:Mucosal-associated invariant T (MAIT) cells acquire effector function in response to proinflammatory signals, which synergize with TCR-mediated signals. We asked if cell-intrinsic regulatory mechanisms exist to curtail MAIT cell effector function akin to the activation-induced expression of inhibitory receptors by conventional T cells. We examined human MAIT cells from blood and oral mucosal tissues by RNA sequencing and found differential expression of immunoregulatory genes, including CTLA-4, by MAIT cells isolated from tissue. Using an ex vivo experimental setup, we demonstrate that inflammatory cytokines were sufficient to induce CTLA-4 expression on the MAIT cell surface in the absence of TCR signals. Even brief exposure to the cytokines IL-12, IL-15, and IL-18 was sufficient for sustained CTLA-4 expression by MAIT cells. These data suggest that control of CTLA-4 expression is fundamentally different between MAIT cells and conventional T cells. We propose that this mechanism serves to limit MAIT cell-mediated tissue damage.

2023-06-23 | GSE235566 | GEO

Human MAIT10 and MAIT17 profiles are effector states directed by the cytokine milieu

Project description:Human MAIT10 and MAIT17 profiles are effector states directed by the cytokine milieu

| PRJNA1006363 | ENA

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

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

TCR and inflammatory signals tune human MAIT cells to exert specific tissue repair and effector functions

Project description:We sought to describe in detail human MAIT cell activation using a transcriptomic approach to define the basic transcriptome of MAIT cells in humans and to determine how this is modulated by activation. Fresh human peripheral blood cells were obtained from three donors, and were magnetically enriched on CD8+ cells, and flow-sorted for live CD161++TCR Va7.2+ MAIT cells. These were cultured in media for 20 hours (“unstimulated”) or in the presence of anti-CD3/CD28 TCR beads (T), cytokines (IL-12, 2ng/ml, IL-18, 50ng/ml, IL-15, 25ng/ml, and TL1A, 100ng/ml), or TCR beads and cytokines combined (TC).

2019-04-17 | GSE129906 | GEO

A Multi-Omics Analysis of Mucosal-Associated-Invariant T cells reveals key drivers of distinct modes of activation

Project description:The function of mucosal-associated invariant T (MAIT) highly depends on the mode of activation, either by recognition of bacterial metabolites via their T cell receptor (TCR) or in a TCR-independent manner via cytokines. The underlying molecular mechanisms are not entirely understood. To define the activation of MAIT cells on the molecular level, we applied a multi-omics approach with untargeted transcriptomics, proteomics and metabolomics. Transcriptomic analysis of E.coli- and TCR-activated MAIT cells showed a distinct transcriptional reprogramming, including altered pathways, transcription factors and effector molecules. We validated the consequences of this reprogramming on the phenotype by proteomics and metabolomics. Thus, and to distinguish between TCR-dependent and -independent activation, MAIT cells were stimulated with IL12/IL18, anti-CD3/CD28 or both. Only a combination of both led to full activation of MAIT cells, comparable to activation by E.coli. Using an integrated network-based approach, we identified key drivers of the distinct modes of activation, including cytokines and transcription factors, as well as negative feedback regulators like TWIST1 or LAG3. Taken together, we present novel insights into the biological function of MAIT cells, which may represent a basis for therapeutic approaches to target MAIT cells in pathological conditions.

2021-06-15 | GSE158439 | GEO

Terminal differentiation and persistence of effector regulatory T cells essential for the prevention of intestinal inflammation [bulk ATAC-seq]

Project description:Regulatory T (Treg) cells represent a specialized CD4+ T cell lineage with essential anti-inflammatory functions. Recent studies of the adaptations of Treg cells to non-lymphoid tissues which enable their specialized immunosuppressive and tissue supportive functions raise questions about the underlying mechanisms of these adaptations and whether they represent stable differentiation or reversible activation states. Using novel genetic tools, we characterized the transcriptional programs of distinct colonic effector Treg cell types. We found that attenuated T cell receptor (TCR) signaling and acquisition of substantial TCR independent functionality appears to facilitate the terminal differentiation of a population of colonic effector Treg cells distinguished by stable expression of immunomodulatory cytokine interleukin-10 (IL-10). Functional studies revealed that this subset of effector Treg cells, but not their expression of IL-10, was indispensable for preventing colitis. These findings suggest core features of terminal differentiation of effector Treg cells in non-lymphoid tissues and their function therein.

2023-07-11 | GSE207966 | GEO

Terminal differentiation and persistence of effector regulatory T cells essential for the prevention of intestinal inflammation [bulk RNA-seq]

2023-07-11 | GSE207965 | GEO

Terminal differentiation and persistence of effector regulatory T cells essential for the prevention of intestinal inflammation [scMultiomics]

2024-10-01 | GSE278537 | GEO