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DHX9 supports iNKT1 lineage maintenance and function [RNA-seq]

ABSTRACT: The terminal maturation of iNKT1 cells requires coordinated transcriptional and cytokine-responsive programs, yet how these programs are supported at lineage-associated regulatory regions remains incompletely understood. In particular, whether the chromatin-associated helicase DHX9 regulates iNKT1 differentiation through these regulatory elements has not been established. In this study, we used a T cell-specific DHX9 deletion mouse model together with transcriptomic and CUT&Tag profiling to evaluate the role of DHX9 in iNKT cell development and function. DHX9 deficiency caused a reduction in terminally mature stage 3 and iNKT1 cells. DHX9 was predominantly detected at promoters, including the Tbx21 and Il2rb loci. Loss of DHX9 attenuated the transcriptional program required to maintain mature iNKT1 cells. DHX9 deficiency also impaired iNKT cell IFN-γ responses and was accompanied by reduced type 1 effector T cell responses. Together, these findings identify DHX9 as a promoter-associated regulator of iNKT1 terminal maturation and provide a basis for investigating how DHX9-associated transcriptional regulation supports innate-like T cell differentiation.

ORGANISM(S): Mus musculus

PROVIDER: GSE346468 | GEO | 2026/09/28

REPOSITORIES: GEO

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DHX9 supports iNKT1 lineage maintenance and function [CUT&Tag]

Project description:The terminal maturation of iNKT1 cells requires coordinated transcriptional and cytokine-responsive programs, yet how these programs are supported at lineage-associated regulatory regions remains incompletely understood. In particular, whether the chromatin-associated helicase DHX9 regulates iNKT1 differentiation through these regulatory elements has not been established. In this study, we used a T cell-specific DHX9 deletion mouse model together with transcriptomic and CUT&Tag profiling to evaluate the role of DHX9 in iNKT cell development and function. DHX9 deficiency caused a reduction in terminally mature stage 3 and iNKT1 cells. DHX9 was predominantly detected at promoters, including the Tbx21 and Il2rb loci. Loss of DHX9 attenuated the transcriptional program required to maintain mature iNKT1 cells. DHX9 deficiency also impaired iNKT cell IFN-γ responses and was accompanied by reduced type 1 effector T cell responses. Together, these findings identify DHX9 as a promoter-associated regulator of iNKT1 terminal maturation and provide a basis for investigating how DHX9-associated transcriptional regulation supports innate-like T cell differentiation.

2026-09-28 | GSE346469 | GEO

Tbet dysregulation compensates for Ets-deficiency in iNKT1 cells

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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

DHX9 supports iNKT1 lineage maintenance and function.

Project description:DHX9 supports iNKT1 lineage maintenance and function.

| PRJNA1525593 | ENA

Exploring the organ specific expression pattern of CD4+iNKT1 cells of C57BL/6 and BALB/c mice.

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2021-04-23 | GSE172169 | GEO

RNA-seq of Tgfbr2-deficient thymic iNKT1 cells

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Project description:The goal of this study was to compare the gene expression program of thymic iNKT1 cells from Control mice to those with a postselection deletion of the transcription factor Ets1 at the single cell level. Ets1-floxed alleles were deleted in iNKT1 cells using Tbx21Cre bacterial artifical chromosome transgenic mice that also carry a Rosa26-floxed-stop-YFP reporter. Control iNKT1 cells were Tbx21Cre+ Rosa26-floxed-stop-YFP reporter+. We isolated all thymic YFP+ cells from Control and cKO mice and processed for scRNA-seq using the 10X Genomics Chromium. Data was processed using the Cell Ranger program for 10X Genomics. . We found that iNKT1 cells lacking Ets1 upregulated Tbx21 and its protein Tbet, many Tbet target genes, and CD8 effector T cell associated genes.

2024-10-10 | GSE278707 | GEO

Ets1 dampens expression of Tbet and CD8- or NK-like effector programing in postselection iNKT1 cells [RNA-seq]

Project description:The goal of this study was to compare the gene expression program of thymic and liver iNKT1 cells from Control mice to those with a postselection deletion of the transcription factor Ets1. Ets1-floxed alleles were deleted in iNKT1 cells using Tbx21Cre bacterial artifical chromosome transgenic mice that also carry a Rosa26-floxed-stop-YFP reporter. Control iNKT1 cells were Tbx21Cre+ Rosa26-floxed-stop-YFP reporter+. We examined gene expression by RNA-sequencing of sorted iNKT1 cells (CD1d-Tet-PBS57+ YFP+) from the thymus and liver. Reads were aligned to the mm10 reference genome using Tophat v 2.1.0. Reads were assigned to genes using the htseq-count tool from HTSeq v 0.6.1 and gene annotations from Ensembl release 78. Differential expression was calculated across 3 independent replicates by EdgeR. We found that iNKT1 cells lacking Ets1 upregulated Tbx21 and its protein Tbet, many Tbet target genes, and CD8 effector T cell associated genes.

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