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Complementary HLH Susceptibility Factors Converge on CD8 T-cell Hyperactivation [bulk RNA-seq]

ABSTRACT: To determine the effects of excess IL-18 and perforin deficiency on CD8 T cells toegther and separately under homeostatic conditions. Mice harboring both excess IL-18 and perforin deficiency (DS) have increased activated (CD44+) CD8 t cells as well as a special CD44low/- CD62L- (DN) population of CD8 T cells. DS mice have CD8 T cells that have specifically upregulated inhibitory receptors Lag3, Havcr2, and Tigit, and the transcription factors Tox and Prdm1. Mice harboring excess IL-18 and partial perforin deficiency (DS-HET) as well as mice with only excess IL-18 (Il18tg) also have these signatures but only in the DN CD8 T cell population. These data support that IL-18 as a potent, independent, and modifiable driver of life-threatening innate nd adaptive hyperinflammation, and support the rationale for an IL-18-driven subclass of hyperinflammation.

ORGANISM(S): Mus musculus

PROVIDER: GSE226125 | GEO | 2023/09/28

REPOSITORIES: GEO

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Project description:T cell receptor (TCR) αβ+ CD4- CD8- double negative T cells represent a rare T cell subset implicated in the pathogenesis of several autoimmune diseases. In this study, we investigated the DNA methylation signature of double negative T cells to gain insight into the epigenetic architecture and transcriptional capacity of peripheral blood primary human double negative T cells compared to autologous CD4+ and CD8+ T cells. We identified 2,984 CG sites across the genome with unique loss of DNA methylation in double negative T cells, and showed significant reduction in mRNA expression of DNA methyltransferases DNMT1, DNMT3A, and DNMT3B. DNA methylation was increased in CD8A/CD8B and CD4 consistent with epigenetic repression of both the CD8 and CD4 genetic loci in double negative T cells. Curiously, we show consistent increase in non-CG methylation in double negative T cells, a finding suggestive of pluripotency and previously only known to occur in embryonic stem cells and developing brain tissue. Network analyses of genes hypomethylated in double negative compared to CD4+ and CD8+ T cells indicate a strong relationship between double negative T cells and functions related to cell-cell interaction, cell adhesion, and cell activation pathways. Our data also suggest a robust pro-inflammatory epigenetic signature in double negative T cells, consistent with a transcriptional permissiveness to produce key inflammatory cytokines including IFNγ, IL-17F, IL-12B, IL-5, IL-18, TNFSF11 (RANKL), and TNFSF13B (BLYS or BAFF). These findings highlight an epigenetic basis for a role of double negative T cells in autoimmunity and extend the potential pathogenic transcriptional capacity of this unique T cell subset. Peripheral blood mononuclear cells (PBMCs) were isolated from fresh blood samples of 7 unrelated healthy women (age range 25-60) (Supplementary Table 1) by Ficoll-gradient centrifugation (GE Healthcare Bio-Sciences AB, Uppsala, Sweden). Subsequently, T cells were negatively-selected using the Human Pan T Cell Isolation II kit (Miltenyi Biotec, Cambridge, MA). T cells were then analyzed and sorted into TCRαβ+ CD4+ T cells, TCRαβ+ CD8+ T cells, and TCRαβ+ DN T cell subsets by flow cytometry. DNA was isolated from CD4+, CD8+, and DN T cell subsets using the DNeasy Blood and Tissue Kit (Qiagen, Valencia, CA), then bisulfite-converted using the EZ DNA Methylation kit (Zymo Research, Irvine, CA) for DNA methylation studies.

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Complementary HLH Susceptibility Factors Converge on CD8 T-cell Hyperactivation [bulk RNA-seq]

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