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Characterization of the developmental landscape of murine RORγt+ iNKT cells

ABSTRACT: Invariant natural killer T cells (iNKT) expressing the retinoic acid receptor-related orphan receptor γt (RORγt) and producing IL-17 represent a minor subset of CD1d-restricted iNKT cells (iNKT17) in C57BL/6J (B6) mice. We aimed in this study to define the reasons for their low distribution and the sequence of events accompanying their normal thymic development. We found that RORγt+ iNKT cells have higher proliferation potential and a greater propensity to apoptosis than RORγt- iNKT cells. These cells do not likely reside in the thymus indicating that thymus emigration, and higher apoptosis potential, could contribute to RORγt+ iNKT cell reduced thymic distribution. Ontogeny studies suggest that mature HSAlow RORγt+ iNKT cells might develop through developmental stages defined by a differential expression of CCR6 and CD138 during which RORγt expression and IL-17 production capabilities are progressively acquired. Finally, we found that RORγt+ iNKT cells perceive a strong TCR signal that could contribute to their entry into a specific Th17 like developmental program influencing their survival and migration. Overall, our study proposes a hypothetical thymic developmental sequence for iNKT17 cells, which could be of great use to study molecular mechanisms regulating this developmental program.

ORGANISM(S): Mus musculus

PROVIDER: GSE139084 | GEO | 2019/10/19

REPOSITORIES: GEO

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RORγt inhibition selectively targets IL-17 producing human iNKT and γδ-T cells enriched in Spondyloarthritis while preserving IL-22 responses

Project description:Dysregulated IL-23/IL-17 responses have been linked to psoriatic arthritis and other forms of spondyloarthritides (SpA). RORγt, the key Thelper17 (Th17) cell transcriptional regulator, is also expressed by subsets of innate-like T cells, including invariant natural killer T (iNKT) and γδ-T cells, but how they contribute to disorders such as SpA is still unclear. Here we describe the presence of particular RORγt+T-betloPLZF- iNKT and γδ-hi T cell subsets in healthy peripheral blood. RORγt+ iNKT and γδ-hi T cells showed profound IL-23 mediated Th17-like immune responses and were clearly enriched within inflamed joints of SpA patients where they act as major IL-17 secretors. SpA derived iNKT and γδ-T cells showed a unique Th17 skewed phenotype and gene expression profile. Strikingly, RORγt inhibition blocked γδ17 and iNKT17 cell function while selectively sparing IL-22+ subsets. Overall, these findings highlight a unique diversity of human RORγt+ T cells and underscore the potential of RORγt antagonism to modulate aberrant type 17 responses.

2018-11-17 | GSE122624 | GEO

TCR signal strength controls thymic differentiation of iNKT cell subsets

Project description:Three major phenotypically and functionally distinct invariant Natural Killer T (iNKT) cell subsets (iNKT1, iNKT17 and iNKT2), each with propensity to traffic to different tissues and to secrete different cytokines upon activation, have been defined. These fate assignments can be conferred upon iNKT cells during development in the thymus, but the cues that direct these decisions remain unclear. Here, we show that T cell antigen receptor (TCR) signal strength governs the development of iNKT cell subsets in the thymus, with high signaling strength necessary for iNKT2 and iNKT17 development. Alteration of TCR diversity and/or signaling dramatically diminished iNKT2 and iNKT17 cell subset development in a cell intrinsic manner. Decreased TCR signaling affected the persistence of Egr2 expression and the upregulation of PLZF both in vivo and in vitro. Genome-wide chromatin accessibility analysis revealed subset-specific activity of regulatory elements associated with unique signatures of transcription factor binding sites. NFAT and Egr binding motifs were found preferentially enriched in chromatin regulatory regions specifically accessible in iNKT2 cells that were lost in iNKT2 cells that had developed with reduced TCR signaling. Altogether, these data suggest a model of iNKT cell subset development where variable TCR signaling induces changes in chromatin accessibility at NFAT and Egr binding sites which exerts a determinative influence on the dynamic of gene enhancer accessibility that affects the developmental fate of iNKT cells.

2018-05-17 | GSE110327 | GEO

TCR signal strength controls thymic differentiation of iNKT cell subsets

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Invariant Natural Killer T Cell Subsets Have Diverse Graft-Versus-Host-Disease-Preventing and Anti-Tumor Effects

Project description:Invariant Natural Killer T (iNKT) cells are a T cell subset with potent immunomodulatory properties. Experimental evidence in mice and observational studies in humans indicate that iNKT cells have antitumor potential as well as the ability to suppress acute and chronic Graft-versus-Host-Disease (GvHD). Murine iNKT cells differentiate during thymic development into iNKT1, iNKT2 and iNKT17 sublineages, which differ transcriptomically and epigenomically, and have subset-specific developmental requirements. Whether distinct iNKT sublineages also differ in their antitumor effect and their ability to suppress GvHD is currently unknown. In this work, we generated highly purified murine iNKTsublineages, characterized their transcriptomic and epigenomic landscape, and assessed specific functions. We demonstrate that iNKT2 and iNKT17, but not iNKT1 cells, efficiently suppress T cell activation in vitro and mitigate murine acute GvHD in vivo. Conversely, we show that iNKT1 cells display the highest antitumor activity against murine B-cell lymphoma cells both in vitro and in vivo. Thus, we demonstrate for the first time that iNKT sublineages have distinct and different functions, with iNKT1 cells having the highest antitumor activity and iNKT2 and iNKT17 cells having immune-regulatory properties. These results have important implications for the translation of i

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Single-cell Transcriptomics Reveal Different Maturation Stages and Sublineages Commitment of Human Thymic Invariant Natural Killer T Cells

Project description:Invariant natural killer T (iNKT) cells are a rare but heterogenous T-cell subset with potent cytotoxic and immunomodulatory properties. During thymic development, murine iNKT cells go through different maturation stages and differentiate into distinct sublineages, namely iNKT1, iNKT2, and iNKT17 cells. Recent reports indicate that iNKT2 cells display immature properties and also give rise to other subsets, whereas iNKT1 cells seem to be terminally differentiated. Whether human iNKT cells follow a similar differentiation model is still unknown. To define the maturation stages and to assess the sublineage commitment of human iNKT cells during thymic development, in the present study we performed single-cell RNA sequencing analysis on human iNKT cells isolated from thymocytes. We show that human iNKT cells displayed heterogeneity and our unsupervised analysis identified two clusters: a first cluster expressed an immature profile with high expression of genes that are important for iNKT cell development and proliferation, whereas a second cluster displayed a mature, terminally differentiated profile. Trajectory analysis suggested an ontological relationship between the two clusters. Evaluation of the expression of sublineage-defining gene sets revealed that the first cluster contained mainly cells with an iNKT2 signature, whereas the more differentiated one contained cells that resembled murine iNKT1 cells. Our data point to the existence of different maturation stages of human thymic iNKT cells and provide evidence for sublineage commitment of iNKT cells in the human thymus.

2022-09-30 | GSE210956 | GEO

Altered thymic differentiation and modulation of arthritis by invariant NKT cells expressing mutant ZAP70 [RNA-Seq]

Project description:Various subsets of invariant natural killer T (iNKT) cells with different cytokine productions develop in the mouse thymus, but the factors driving their differentiation remain unclear. Here we show that hypomorphic alleles of Zap70 or chemical inhibition of Zap70 catalysis lead to an increase of IFN-g-producing iNKT cells (NKT1 cells), suggesting NKT1 cells may require a lower TCR signal threshold. Zap70 mutant mice develop IL-17-dependent arthritis. iNKT cells and therapeutic induction of IFN-g secretion by activating iNKT cells are protective in this model, but the representation of IFNg versus IL-17 secreting iNKT cells in the joint change in favor of IL-17 producers as disease worsened. NKT1 cells are also present in the synovial fluid of arthritis patients, where they could be beneficial. Our data therefore suggest that TCR signal strength during thymic differentiation may influence not only IFNg production, but also the protective function of iNKT cells in arthritis.

2018-05-17 | GSE114555 | GEO

Altered thymic differentiation and modulation of arthritis by invariant NKT cells expressing mutant ZAP70 [II]

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A comparison of the transcriptional profiles of invariant NKT cells derived from Wild type and Eomes conditional knockout mice

Project description:Functional subsets of iNKT cells, NKT1, NKT2 and NKT17, have been reported to arise during the thymus to peripheral differentiation stages. The key transcription factors for NKT1, NKT2 and NKT17 development in the thymus have been identified as T-bet, Gata3 and Rorγt, respectively. In contrast, these iNKT cell subsets can also undergo further differentiation in the periphery. Eomesodermin (Eomes) is a T-box transcription factor with high homology to T-bet and is expressed by activated CD8+ T cells as well as in resting and activated NK cells. However, its role in invariant (i)NKT cells remains unknown. Here, we show the impact of Eomes on iNKT cells in the thymus and peripheral tissue using conditional knockout (Eomes-cKO) mice. Eomes regulates the differentiation of NKT1 cells in the thymus. In the peripheral tissue, Klrg1+ iNKT1 cells are generated in lung after vaccination with -GalCer-pulsed DCs (DC/Gal) as memory like iNKT cells. In the current study, we found that Eomes also regulates their differentiation into memory-like KLRG1+iNKT cells in the periphery.

2019-05-09 | GSE128069 | GEO

Essential functions for ID proteins at multiple checkpoints in natural killer T cell development

Project description:Thymic iNKT cell development is divided into four stages (stage 0-3) that are characterised, in C57BL/6 mouse strain, by the differential expression of surface markers, such as CD24, CD44 and NK1.1. During transition from immature to mature iNKT cell subsets, gene expression is tightly regulated. Here, we used microarray analysis to detail the influence of the transcriptional regulator ID3 during iNKT cell maturation in the thymus. Stage 1 (Tet+CD24-CD44-NK1.1-) and Stage 2 (Tet+CD24-CD44+NK1.1-) iNKT cells from WT and Id3KO thymi were FACS sorted for RNA extraction and Affymetrix hybridisation.

2013-11-19 | E-GEOD-50933 | biostudies-arrayexpress

Gene expression profiling of WT or Dicer KO iNKT cells and T cells

Project description:iNKT cells are a T lymphocyte subset displaying an innate effector phenotype that is acquired through a thymic developmental program controlled by microRNAs (miRNAs). iNKT cells lacking all miRNAs by the deletion of Dicer (Dicer KO) are markedly reduced and display a complete maturation block. In this study, we sought to gain insight into the miRNA-regulated genetic program required for iNKT cell development. By systemic analysis, we identified transcripts differentially expressed between thymic WT or Dicer KO iNKT cells and targeted by the iNKT cell-specific miRNAs. TGF-βRII, a molecule critically implicated in iNKT cell maturation, was found upregulated in Dicer KO iNKT cells together with increased TGF-β-dependent signaling. miRNAs belonging to the paralog miR-106a~363, miR-106b~25 and miR-17~92 clusters were predicted to target TGF-βRII mRNA during iNKT cell development. Thymic iNKT cells lacking all three miRNA clusters displayed both increased TGF-βRII expression and signaling and a maturation block, recapitulating those found in Dicer KO iNKT cells. Consistently, inhibition of TGF-β-dependent signaling in the absence of miRNAs, by crossing TGF-βRII KO and Dicer KO mice, rescued iNKT cell maturation. Collectively, our results highlight a fundamental requirement of the modulation of TGF-β-dependent signaling by miRNAs for iNKT cell development

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