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IL-23 tunes inflammatory functions of human MAIT cells

ABSTRACT: IL-23 signaling plays a key role in the pathogenesis of chronic inflammatory and infectious diseases, yet the cellular targets and signaling pathways affected by this cytokine remain poorly understood. We show that IL-23 receptors are expressed on the large majority of human MAIT, but not of conventional T cells, suggesting that these innate-like T cells are critical mediators of IL-23 functions. In this study, we investigated the effects of IL-23 on human MAIT cell transcriptional and chromatin accessibility profiles, using RNA- and CITE-seq and ATAC-seq, respectively. Protein and transcriptional profiling at the population and single cell level demonstrates that stimulation with IL-23 or the structurally related cytokine IL-12 drives distinct functional profiles, revealing a high level of plasticity of MAIT cells. IL-23, in particular, affects key molecules and pathways related to autoimmunity and cytotoxic functions. Integrated analysis of transcriptomic and chromatin accessibility shows that AP-1 transcription factors constitute a key regulatory node of the IL-23 pathway in MAIT cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE270499 | GEO | 2025/01/07

REPOSITORIES: GEO

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IL-23 tunes inflammatory functions of human MAIT cells

Project description:IL-23 signaling plays a key role in the pathogenesis of chronic inflammatory and infectious diseases, yet the cellular targets and signaling pathways affected by this cytokine remain poorly understood. We show that IL-23 receptors are expressed on the large majority of human MAIT, but not of conventional T cells, suggesting that these innate-like T cells are critical mediators of IL-23 functions. In this study, we investigated the effects of IL-23 on human MAIT cell transcriptional and chromatin accessibility profiles, using RNA- and CITE-seq and ATAC-seq, respectively. Protein and transcriptional profiling at the population and single cell level demonstrates that stimulation with IL-23 or the structurally related cytokine IL-12 drives distinct functional profiles, revealing a high level of plasticity of MAIT cells. IL-23, in particular, affects key molecules and pathways related to autoimmunity and cytotoxic functions. Integrated analysis of transcriptomic and chromatin accessibility shows that AP-1 transcription factors constitute a key regulatory node of the IL-23 pathway in MAIT cells.

2025-01-06 | GSE269978 | GEO

Multiomic analysis reveals decidual-specific transcriptional programing of MAIT cells

Project description:Problem: Mucosal-Associated Invariant T (MAIT) cells have been recently identified at the maternal-fetal interface. However, transcriptional programming of decidual MAIT cells in pregnancy remains poorly understood. Method of Study: We employed a multiomic approach to address this question. Mononuclear cells from the decidua basalis and parietalis, and control PBMCs, were analyzed via flow cytometry to investigate MAIT cells in the decidua and assess their transcription factor expression. In a separate study, both decidual and matched peripheral MAIT cells were analyzed using Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) coupled with gene expression analysis. Lastly, decidual MAIT cells were stimulated with E. coli and expression of MR1 by antigen presenting cells was measured to evaluate decidual MAIT cell function. Results: First, we identified MAIT cells in both the decidua basalis and parietalis. CITE-seq, coupled with scRNAseq gene expression analysis, highlighted transcriptional programming differences between decidual and matched peripheral MAIT cells at a single cell resolution. Transcription factor expression analysis further highlighted transcriptional differences between decidual MAIT cells and non-matched peripheral MAIT cells. Functionally, MAIT cells are skewed towards IFNg and TNFa production upon stimulation, with E. coli leading to IFNg production. Lastly, we demonstrate that MR1, the antigen presenting molecule restricting MAIT cells, is expressed by decidual APCs. Conclusion: MAIT cells are present in the decidua basalis and obtain a unique gene expression profile. The presence of MR1 on APCs coupled with in vitro activation by E. coli suggests that MAIT cells might be involved in tissue-repair mechanisms at the maternal-fetal interface.

2021-09-07 | GSE183421 | GEO

Outcome of SARS-CoV-2 infection is linked to MAIT cell activation and cytotoxicity

Project description:Immune system dysfunction is paramount in Coronavirus disease 2019 (COVID-19) severity and fatality rate. MAIT cells are innate-like T cells involved in mucosal immunity and protection against viral infections. Here, we studied the immune cell landscape, with emphasis on MAIT cells, in cohorts of 208 patients at various stages of disease activity. MAIT cell frequency is strongly reduced in blood. They display a strong activated and cytotoxic phenotype that is more pronounced in lungs. Blood MAIT cell alterations positively correlate with other innate cell activation; pro-inflammatory cytokines, notably IL-18; and with the severity and mortality of SARS-CoV-2 infection. We also identified a monocyte/macrophage Interferon-a-IL-18 cytokine shift and the ability of infected macrophages to induce cytotoxicity of MAIT cells in an MR1-dependent manner. Together our results suggest that altered MAIT cell functions due to IFN-a-IL-18 imbalance contribute to disease severity and their therapeutic manipulation might prevent deleterious inflammation in COVID-19 aggravation.

2021-01-08 | GSE164386 | GEO

Mouse Th17 T cells, IL-23 stimulated

Project description:Interleukin 23 (IL-23) triggers pathogenic features in pro-inflammatory, IL-17-secreting T cells (Th17 and Tγδ17) that play a key role in the development of inflammatory diseases. However, the IL-23 signaling cascade remains largely undefined. Here we used quantitative phosphoproteomics to characterize IL-23 signaling in primary murine Th17 cells. We quantified 6,888 phosphorylation sites in Th17 cells, and found 168 phosphorylations regulated upom IL-23 stimulation. IL-23 increased the phosphorylation of the myosin regulatory light chain (RLC), an actomyosin contractibility marker, in Th17 and Tγδ cells. IL-23-induced RLC phosphorylation required JAK2 and ROCK catalytic activity, and the study of the IL-23/ROCK axis revealed an unexpected role of IL-23 in the migration of Tγδ17 and Th17 cells. Moreover, pharmacological inhibition of ROCK reduced Tγδ17 recruitment to inflamed skin upon challenge with inflammatory agent Imiquimod. This work: i) provides new insights into phosphorylation networks that control Th17 cells, ii) widely expands the current knowledge on IL-23 signaling, and iii) contributes to the increasing list of immune cells subsets characterized by global phosphoproteomic approaches.

2020-03-25 | PXD016633 | Pride

Interleukin-23-induced transcription factor Blimp1 promotes pathogenicity of T helper 17 cells

Project description:Interleukin-23 (IL-23) is a pro-inflammatory cytokine required for the pathogenicity of T helper 17 (Th17) cells but the molecular mechanisms governing this process remain unclear. We identified the transcription factor Blimp-1 (Prdm1) as a key IL-23-induced factor that drove the inflammatory function of Th17 cells. In contrast to thymic deletion of Blimp-1, which causes T cell development defects and spontaneous autoimmunity, peripheral deletion of this transcription factor resulted in reduced Th17 activation and reduced severity of autoimmune encephalomyelitis. Furthermore, genome wide occupancy and overexpression studies in Th17 cells revealed that Blimp-1 co-localized with transcription factors RORÎ³t, STAT-3 and p300 at the Il23r, Il17a/f and Csf2 cytokine loci to enhance their expression. Blimp-1 also directly bound to and repressed cytokine loci Il2 and Bcl6. Taken together, our results demonstrate that Blimp-1 is an essential transcription factor downstream of IL-23 that acts in concert with RORÎ³t to activate the Th17 inflammatory program. Genome-wide binding analysis of Blimp1 from in vitro generated T effector and regulatory cells

2016-06-15 | E-GEOD-75724 | biostudies-arrayexpress

MAIT cell RNA sequencing

Project description:Obesity underpins the development of numerous chronic diseases such as type II diabetes mellitus. It is well established that obesity negatively alters immune cell frequencies and functions. Mucosal Associated Invariant T (MAIT) cells are a population of innate T cells, which we have previously reported are dysregulated in obesity, with altered circulating and adipose tissue frequencies and a reduction in their IFN-gamma production, which is a critical effector function of MAIT cells in host defence. Hence there is increased urgency to characterise the key molecular mechanisms that drive MAIT cell effector functions, and to identify those which are impaired in the obesity setting. In this study, we found that MAIT cells significantly upregulate their rates of glycolysis upon activation in an mTORC1 dependent manner and this is essential for MAIT cell IFN-g production. Furthermore, we show that mTORC1 activation is dependent on amino acid transport via SLC7A5. In obese patients, using RNA sequencing, Seahorse analysis and a series of in vitro experiments, we demonstrate that MAIT cells isolated from obese adults display defective glycolytic metabolism, mTORC1 signalling and SLC7A5 amino acid transport. Collectively our data details the intrinsic metabolic pathways controlling MAIT cell cytokine production and highlights mTORC1 as an important metabolic regulator that is impaired in obesity, leading to altered MAIT cell responses. We report on MAIT cells isolated from lean and obese adults

2019-04-16 | GSE126169 | GEO

Interleukin-23-induced transcription factor Blimp1 promotes pathogenicity of T helper 17 cells

Project description:Interleukin-23 (IL-23) is a pro-inflammatory cytokine required for the pathogenicity of T helper 17 (Th17) cells but the molecular mechanisms governing this process remain unclear. We identified the transcription factor Blimp-1 (Prdm1) as a key IL-23-induced factor that drove the inflammatory function of Th17 cells. In contrast to thymic deletion of Blimp-1, which causes T cell development defects and spontaneous autoimmunity, peripheral deletion of this transcription factor resulted in reduced Th17 activation and reduced severity of autoimmune encephalomyelitis. Furthermore, genome wide occupancy and overexpression studies in Th17 cells revealed that Blimp-1 co-localized with transcription factors RORγt, STAT-3 and p300 at the Il23r, Il17a/f and Csf2 cytokine loci to enhance their expression. Blimp-1 also directly bound to and repressed cytokine loci Il2 and Bcl6. Taken together, our results demonstrate that Blimp-1 is an essential transcription factor downstream of IL-23 that acts in concert with RORγt to activate the Th17 inflammatory program.

2016-06-15 | GSE75724 | GEO

Gene expression profiles of MAIT cells, MAIT-iPSCs, hiPSCs, hESCs, and reMAIT cells

Project description:To show the similarity among MAIT-iPSCs, hiPSCs and hESCs and the gradual change of global gene expression of reMAIT cells along with differentiation, this experiment was designed. MAIT cells, MAIT-iPSCs, hiPSCs, hESCs, MAIT cells, and reMAIT cells at the several differerent stages of differentiation were collected. Then, they were applied in this experiment.

2013-03-21 | E-GEOD-44559 | biostudies-arrayexpress

Di- and trimeric biological switches made of nanobody-cytokine receptor fusion proteins simulate IL-23 signaling

Project description:Cytokine-induced signal transduction is executed by natural biological switches, which among many others control immune related processes. To construct a biological device, that simulates cytokine signaling, we utilized nanobodies to generate synthetic cytokine receptors (SyCyR). High affinity GFP- and mCherry-nanobodies were selected and extracellularly fused to trans-membrane and intracellular domains of IL-23 cytokine receptors. Soluble homo- and heterodimeric GFP:mCherry fusion proteins served as SyCyR ligands. Heterodimeric GFP-mCherry and homodimeric GFP fusion proteins efficiently phenocopied IL-23 signal transduction, respectively, as demonstrated by STAT3-, ERK- and Akt-activation, SOCS3 expression and transcriptome profiling. Interestingly, the homodimeric GFP fusion protein induced IL-23 receptor homo-dimerization and activation of IL-23-like signal transduction

2018-04-17 | GSE101569 | 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

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