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Gene Regulation by Histone Deacetylase 7 During Invariant Natural Killer T Cell Development

ABSTRACT: We have found that the signal-dependent chromatin modulator Histone Deacetylase 7 interacts with and corepresses the signature transcription factor of invariant natural Killer T (iNKT) cells, ZBTB16. This study was designed to determine the global effect on transcription of a gain-of-function mutant of HDAC7 during iNKT cell development and function. Va14/Ja18 T cell receptor transgenic thymocytes and splenocytes, which develop preferentially into iNKT cells, were profiled by RNA-seq with and without expression of a gain-of-functon HDAC7 transgene (HDAC7dP)

ORGANISM(S): Mus musculus

PROVIDER: GSE105026 | GEO | 2018/05/08

REPOSITORIES: GEO

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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

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

Critical role for very-long chain sphingolipids in invariant natural killer T cell development and homeostasis

Project description:The role of sphingolipids (SLs) in the immune system has come under increasing scrutiny recently due to the emerging contributions that these important membrane components play in regulating a variety of immunological processes. The acyl chain length of SLs appears particularly critical in determining SL function. Here we show a role for very-long acyl chain SLs (VLC-SLs) in invariant natural killer T (iNKT) cell maturation in the thymus and homeostasis in the liver. Ceramide synthase 2 (CerS2) null mice, which lack VLC-SLs, were susceptible to a hepatotropic strain of lymphocytic choriomeningitis virus, which is due to a reduction in the number of iNKT cells. Bone marrow chimera experiments indicated that hematopoietic-derived VLC-SLs are essential for maturation of iNKT cells in the thymus, whereas parenchymal-derived VLC-SLs are crucial for iNKT cell survival and maintenance in the liver. Our findings suggest a critical role for VLC-SL in iNKT cell physiology.

2017-10-15 | GSE104205 | GEO

Single-cell RNA-seq of mouse thymus iNKT cells

Project description:Invariant natural killer T cells (iNKT) cells are innate-like T cells, selected from thymic cortex-resident CD4+CD8+ double positive (DP) thymocytes. Despite major advances in the understanding of iNKT cells development, the heterogeneity of iNKT subsets and underlying molecular programs that guide iNKT cell-lineage remain unclear.

2022-08-10 | GSE130184 | 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

Generation of Allogeneic Hematopoietic Stem Cell-Engineered Invariant Natural Killer T cells for Off-the-Shelf Immunotherapy [VDJ-seq]

Project description:While T cell-based immunotherapies have shown promising clinical responses, current cancer treatments are restricted to autologous cellular products due to the risk of graft-versus-host disease (GvHD) by allogeneic cell transfer. Invariant natural killer T (iNKT) cells are ideal cell carriers for developing off-the-shelf allogeneic cellular therapy because they are powerful immune cells targeting a broad range of cancers without causing GvHD. However, current immunotherapies using iNKT cells are impeded by their extremely low number in cancer patients. In this study, we aimed to overcome this limitation by generating a large number of iNKT cells through TCR engineering of human hematopoietic stem cells (HSCs) and differentiation of HSCs to iNKT cells in an in vitro cultured system. Additionally, Chimeric antigen receptor (CAR) engineering and the CRISPR-Cas9 gene editing tool were utilized to enhance the tumor killing efficacy of iNKT cells and eliminate HLA molecules on their surface, making the cellular product suitable for cancer therapy and allogeneic adoptive transfer. Our results demonstrated successful generation of the promising off-the-shelf B cell maturation antigen (BCMA)-CAR engineered iNKT cells for treating multiple myeloma, and the same strategy will be applied to multiple cellular products for treating other cancers.

2021-12-01 | GSE164500 | GEO

Generation of Allogeneic Hematopoietic Stem Cell-Engineered Invariant Natural Killer T cells for Off-the-Shelf Immunotherapy [RNA-seq]

2021-12-01 | GSE164425 | GEO

Immunomodulatory potential of in vivo Natural Killer T (NKT) activation by NKTT320 in Mauritian-origin cynomolgus macaques

Project description:Invariant natural killer T-lymphocytes (iNKT) are unique immunomodulatory innate T-cells with an invariant TCR recognizing glycolipids presented on MHC class-I-like CD1d molecules. Activated iNKT rapidly secrete pro-and anti-inflammatory cytokines, potentiate immunity, and modulate inflammation. Here, we report the effects of in vivo iNKT activation in Mauritian-origin cynomolgus macaques by a humanized monoclonal antibody, NKTT320, that binds to the invariant region of the iNKT TCR. NKTT320 led to rapid iNKT activation, increased polyfunctionality, and elevation of multiple plasma analytes within 24 hours of administration. Flow cytometry and RNA-Seq confirmed downstream activation of multiple immune subsets, enrichment of JAK/STAT and PI3K/AKT pathway genes, and upregulation of inflammation-modulating genes. NKTT320 also increased iNKT frequency in adipose tissue without iNKT anergy. Our data indicate that NKTT320 has a sustained effect on in vivo iNKT activation, potentiation of innate and adaptive immunity, and resolution of inflammation, which supports its future use as an immunotherapeutic.

2022-01-25 | GSE194235 | GEO

Expression data from invariant natural killer T (iNKT) cells in spleen and adipose tissue

Project description:Adipose tissue iNKT cells have different functions than iNKT cells in the blood and other organs. We used microarrays to detail the global gene expression profiles that might underlie these phenotypic and functional differences in adipose iNKT cells compared to splenic iNKT cells.

2014-12-01 | GSE63358 | GEO

Global epigenetic stability of liver-resident invariant natural killer T cells in response to cues capable of inducing transcriptional re-programming

Project description:Unlike conventional CD4+ T cells, which are phenotypically and functionally plastic, invariant NKT (iNKT) cells generally exist in a terminally differentiated state. Although peripheral CD4+ T cells can acquire alternative epigenetic states in response to different cues, it remains unclear whether peripheral iNKT cells are epigenetically stable or maleable. Repetitive encounters of liver-resident iNKT cells (LiNKTs) with galactosylceramide (aGalCer)/CD1d-coated nanoparticles (NPs) can trigger their differentiation into a LiNKT cell subset (LiNKTR1) expressing a T regulatory type 1 (TR1)-like transcriptional signature. Here we use a broad range of omics tools to dissect the epigenetic underpinnings of the LiNKT-LiNKTR1 transdifferentiation process as compared to those underlying the T-conv-to-T-follicular helper (TFH) and TFH-to-TR1 differentiation pathways. We show that LiNKTR1 cell generation is partially associated with treatment induced hypo-methylation of gene bodies and regulatory elements of upregulated genes, in the absence of significant changes in chromatin exposure, deposition of expression-promoting histone marks, or removal of their repressive counterparts from bivalent regulatory elements. In contrast, the Tconv-TFH differentiation process involves extensive remodeling of the chromatin and the acquisition of a broad repertoire of epigenetic modifications that are then inherited by TFH cell-derived TR1 cell progeny. These results suggest that peripheral tissue-resident iNKT cells, unlike conventional T cells but like TFH cells, are epigenetically stable and that such stability contributes to their phenotypic and functional stability.

2024-10-02 | GSE250192 | GEO

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