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TCR signal strength controls thymic differentiation of iNKT cell subsets

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE110327 | GEO | 2018/05/17

REPOSITORIES: GEO

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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.

2018-05-18 | GSE111427 | GEO

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

2021-04-23 | GSE172169 | GEO

microRNA-155 controls iNKT cell development and lineage differentiation by coordinating multiple regulating pathways

Project description:The development of invariant natural killer T (iNKT) cells requires a well-attuned set of transcription factors, but how these factors are regulated and coordinated remains poorly understood. MicroRNA-155 (miR-155) is a key regulator of numerous cellular processes that affects cell development and homeostasis. Here, we found that the miR-155 was highly expressed in early iNKT cells upon thymic section, and then its expression is gradually downregulated during iNKT cell development. However, the mice with miR-155 germline deletion had normal iNKT cell development. To address if downregulated miR-155 is required for iNKT cell development, we made a CD4Cre.miR-155 knock-in (KI) mouse model with miR-155 conditional overexpression in the T cell lineage. Upregulated miR-155 led to interruption of iNKT cell development, diminished iNKT17 and iNKT1 cells, augmented iNKT2 cells, and these defects were cell-intrinsic. Furthermore, defective iNKT cells in miR-155KI mice resulted in the secondary innate-like CD8 T cell development. Mechanistically, miR-155 modulated multiple targets and signaling pathways to fine tune iNKT cell development. MiR-155 modulated Jarid2, a critical component of a histone modification complex, and Tab2, the upstream activation kinase complex component of NF-kB, which function additively in iNKT development and in promoting balanced iNKT1/iNKT2 differentiation. In addition, miR-155 also targeted Rictor, a signature component of mTORC2 that controls iNKT17 differentiation. Taken together, our results indicate that miR-155 serves as a key epigenetic regulator, coordinating multiple signaling pathways and transcriptional programs to precisely regulate iNKT cell development and functional lineage, as well as secondary innate CD8 T cell development.

2021-12-21 | GSE162613 | GEO

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

Gene expression signatures of iNKT-subpopulations sorted from thymus of BALB/c and C57BL/6 mice

Project description:iNKT cells can be classified based on functional criteria into iNKT1, iNKT2 and iNKT17 cells, respectively. Here, a protocol was applied allowing sorting of living cells from thumus of BALB/c and C57BL/6 mice. The obtained gene expression profiles confirmed already existing information regarding the iNKT subtypes and will therefore provide useful hints for further investigations.

2016-10-05 | GSE69120 | GEO

Characterization of the developmental landscape of murine RORγt+ iNKT cells

Project description: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.

2019-10-19 | GSE139084 | GEO

Kidins220 and Aiolos promote thymic iNKT cell development by reducing TCR signals

Project description:Development of T cells is controlled by the signal strength of the TCR. The scaffold protein Kinase D-interacting substrate of 220 kDa (Kidins220) binds to the TCR; however, its role in T cell development was unknown. Here, we show that T cell-specific Kidins220 knock-out (T-KO) mice have strongly reduced invariant natural killer T (iNKT) cell numbers and modest decreases in conventional T cells. Enhanced apoptosis due to increased TCR signaling in T-KO iNKT thymocytes of developmental stage 2 and 3 shows that Kidins220 downregulates TCR signaling at these stages. scRNAseq indicated that the transcription factor Aiolos is downregulated in Kidins220-deficient iNKT cells. Analysis of an Aiolos KO demonstrated that Aiolos is a downstream effector of Kidins220 during iNKT cell development. In the periphery, T-KO iNKT cells show reduced TCR signaling upon stimulation with α-galactosylceramide, suggesting that Kidins220 promotes TCR signaling in peripheral iNKT cells. Thus, Kidins220 reduces or promotes signaling dependent on the iNKT cell developmental stage.

2024-03-11 | GSE253196 | GEO

Mitochondrial Metabolism is Essential for Invariant Natural Killer T Cell Development and Function

Project description:Conventional T cell fate and function are determined by coordination between cellular signaling and metabolism. Invariant natural killer T (iNKT) cells are a subset of “innate-like” pre-activated T cells whose dependence on mitochondrial metabolism remains elusive. Here, we showed that mature iNKT cells have reduced mitochondrial respiratory reserve and iNKT cell development was highly sensitive to perturbation of mitochondrial function. Mice with T cell-specific ablation of Rieske Iron-Sulphur protein (T-Uqcrfs1-/-), an essential subunit of mitochondrial complex III, had a dramatic reduction of iNKT cells in the thymus and periphery, but minimal effects on conventional T cell development. Residual iNKT cells in T-Uqcrfs1-/- mice retained ability to proliferate but exhibited increased apoptosis, decreased TCR signaling and impaired responses to TCR and IL-15 stimulation. Furthermore, knocking down RISP in mature iNKT cells diminished their cytokine production, correlating with reduced NFATC2 activity. Collectively, our data demonstrate a critical role for mitochondrial metabolism in iNKT cell development and activation outside of supporting bioenergetic demands.

2021-03-12 | GSE157283 | GEO

Single-cell RNA-sequencing data and functional analysis revealed that ACC1, a rate limiting enzyme of fatty acid biosynthesis, is responsible for survival of thymic iNKT cells.

Project description:Invariant Natural Killer T (iNKT) cells are a unique subset of T lymphocytes with a memory like phenotype which express invariant T cell receptor (TCR) chain comprised of a Vα14-Jα18 rearrangement in mice. In the present study, we characterize the transcriptomes of thymic iNKT cells at the single cell level to reveal the underlying metabolic adaptation that exists over the course of iNKT cell development.

2023-12-29 | GSE248939 | GEO

Direct regulation of T cell exhaustion by NFAT [RNA-Seq]

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2015-02-13 | E-GEOD-64408 | biostudies-arrayexpress

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