Human MAIT10 and MAIT17 profiles are effector states directed by the cytokine milieu
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1006363 | ENA |
REPOSITORIES: ENA
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Project description: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.
2025-01-19 | GSE241077 | GEO
Project description:Mucosal-associated invariant T (MAIT) cells are unconventional T cells that mediate rapid antimicrobial immune responses to antigens derived from microbial riboflavin pathway metabolites presented by the evolutionarily conserved MR1 molecules. MAIT cells represent a large pre-expanded T cell subset in humans and are involved in both protective immunity and inflammatory immunopathology. However, what controls the functional heterogeneity of human MAIT cell responses is still largely unclear. Here, combining functional and transcriptomic analyses, we investigate how MAIT cell response programs are influenced by the cytokine milieu at the time of antigen recognition. Activation by MR1-presented antigen together with IL-12 induces intermediate levels of IFNγ and TNF, as well as a regulatory profile with substantial IL-10 production and elevated expression of TIM-3, LAG-3, and PD-1. Activation by the combination of antigen and IL-12 induces a c-MAF-dependent program required for IL-10 production. The MAIT cell-derived IL-10 mediates both autocrine and paracrine immune regulation. In contrast, coactivation of MAIT cells with IL-18 induces IL-17, GM-CSF, IFNγ, and TNF, without IL-10. Notably, IL-18 dominantly counteracts IL-10 expression. The activation states biased toward IL-10 or IL-17 production are reversible and do not represent stable subsets. Finally, MR1-restricted TCR-mediated activation without cytokine coactivation drives primarily granzyme B cytolytic arming. Altogether, these findings demonstrate that human MAIT cells adapt their functional effector response during antigen recognition to cytokine cues in the microenvironment, and identify programs biased toward either regulatory c-MAF-dependent IL-10 expression, or an inflammatory IL-17 and GM-CSF profile.
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Project description:Macrophage ontogeny and local cytokines jointly govern tumor-associated macrophage behaviour, yet how these signals integrate to generate pro- or antitumor outputs is unknown. Here, we apply a reductionist, multi-scale pipeline to systematically map eight reference macrophage states generated by ex vivo differentiation of mouse bone marrow cells with macrophage colony-stimulating factor (M-CSF) or granulocyte-macrophage CSF (GM-CSF) and subsequent cytokine polarization (IFN-gamma, IL-4, IL-10, TGF-beta). We integrated transcriptomic, 3D spheroid, and in vivo metastatic analyses to discover a lineage dependent polarity switch: IL-4 drives an ARG1+, tumor-supportive programme in M-CSF macrophages but, via NfkB, induces a CCR7+ inflammatory phenotype in GM-CSF macrophages. IFN-gamma uniformly activates STAT1/IRF pathways, maintaining antitumor profiles, whereas IL-10 and TGF-beta maximally evoke SPP1+ immunosuppressive signatures after GM-CSF priming. Functional assays confirmed these transcriptional states dictate opposite effects on tumor growth, invasion, and pulmonary metastasis. Integration of all parameters yielded an "ontogeny cytokine code" that predicts macrophage function based on developmental history and cytokine milieu. Identifying CSF-defined lineage as a master regulator of macrophage heterogeneity provides a blueprint for precision immunotherapies that reprogram macrophages in solid tumors. This SuperSeries is composed of the SubSeries listed below.
2025-09-30 | GSE304868 | GEO
Project description:Understanding the mechanisms underlying the acquisition and maintenance of effector function during T cell differentiation is important to unraveling how these processes can be dysregulated in the context of disease and manipulated for therapeutic intervention. Herein, we report the identification of a novel regulator of murine T cell differentiation through the evaluation of a previously unreported activity of the kinase inhibitor, BioE-1197. Specifically, we demonstrate liver kinase B1 (LKB1) mediated activation of salt-inducible kinases (SIKs) epigenetically regulates cytokine recall potential in effector CD8+ and Th1 cells. Evaluation of this phenotype revealed SIK mediated phosphorylation dependent stabilization of histone deacetylase 7 (HDAC7) occurred during late-stage effector differentiation. HDAC7 stabilization increased nuclear HDAC7 levels which correlated with both global and cytokine loci specific reductions in the activating transcription mark, histone 3 lysine 27 acetylation (H3K27Ac). Accordingly, HDAC7 stabilization diminished transcriptional induction of cytokine upon re-stimulation. Inhibition of this pathway during differentiation produced effector T cells epigenetically poised for enhanced cytokine recall. This work identifies a novel target for enhancing effector T cell functionality.
2023-09-12 | GSE242482 | GEO
Project description:Carbo2013 - Cytokine driven CD4+ T Cell differentiation and phenotype plasticity
CD4+ T cells can differentiate into different phenotypes
depending on the cytokine milieu. Here a computational and mathematical model with sixty ordinary differential equations representing a CD4+ T cell differentiating into either Th1, Th2, Th17 or iTreg cells, has been constructed.
The model includes cytokines,
nuclear receptors and transcription factors that define fate
and function of CD4+ T cells. Computational simulations
illustrate how a proinflammatory Th17 cell can undergo
reprogramming into an anti-inflammatory iTreg phenotype
following PPARc activation.
This model is described in the article:
Systems Modeling of Molecular Mechanisms Controlling Cytokine-driven CD4+ T Cell Differentiation and Phenotype Plasticity.
Carbo A, Hontecillas R, Kronsteiner B, Viladomiu M, Pedragosa M, Lu P, Philipson CW, Hoops S, Marathe M, Eubank S, Bisset K, Wendelsdorf K, Jarrah A, Mei Y, Bassaganya-Riera J
PLoS Computational Biology [2013, 9(4):e1003027]
Abstract:
Differentiation of CD4+ T cells into effector or regulatory phenotypes is tightly controlled by the cytokine milieu, complex intracellular signaling networks and numerous transcriptional regulators. We combined experimental approaches and computational modeling to investigate the mechanisms controlling differentiation and plasticity of CD4+ T cells in the gut of mice. Our computational model encompasses the major intracellular pathways involved in CD4+ T cell differentiation into T helper 1 (Th1), Th2, Th17 and induced regulatory T cells (iTreg). Our modeling efforts predicted a critical role for peroxisome proliferator-activated receptor gamma (PPARγ) in modulating plasticity between Th17 and iTreg cells. PPARγ regulates differentiation, activation and cytokine production, thereby controlling the induction of effector and regulatory responses, and is a promising therapeutic target for dysregulated immune responses and inflammation. Our modeling efforts predict that following PPARγ activation, Th17 cells undergo phenotype switch and become iTreg cells. This prediction was validated by results of adoptive transfer studies showing an increase of colonic iTreg and a decrease of Th17 cells in the gut mucosa of mice with colitis following pharmacological activation of PPARγ. Deletion of PPARγ in CD4+ T cells impaired mucosal iTreg and enhanced colitogenic Th17 responses in mice with CD4+ T cell-induced colitis. Thus, for the first time we provide novel molecular evidence in vivo demonstrating that PPARγ in addition to regulating CD4+ T cell differentiation also plays a major role controlling Th17 and iTreg plasticity in the gut mucosa.
Author's comment:
CD4+ T cell computational model (Version 1.4)
Steady state corrected. There was a problem in the internalization of IL-17 in its mathematical function.
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2024-09-02 | BIOMD0000000451 | BioModels
Project description:Cytokine–ontogeny interaction shapes macrophage transcriptional states
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Project description:Memory T cells are heterogeneous in terms of their phenotype and functional properties. We investigated the molecular profiles of human CD8 naïve (TN), central memory (TCM), effector memory (TEM), and effector memory RA (TEMRA) T cells using gene expression microarrays and phospho-protein-specific intracellular flow cytometry. We demonstrate that TCM have a gene expression and cytokine signaling signature that lies between that of TN and TEM or TEMRA cells, whereas TEM and TEMRA are closely related. Our data define the molecular basis for the different functional properties of central and effector memory subsets. We show that TEM and TEMRA cells strongly express genes with known importance in CD8 T cell effector function. In contrast, TCM are characterized by high basal and cytokine-induced STAT5 phosphorylation, reflecting their capacity for self-renewal. Altogether, our results distinguish TCM and TEM/TEMRA at the molecular level and are consistent with the concept that TCM represent memory stem cells.
2005-01-01 | E-TABM-40 | biostudies-arrayexpress