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Memory-like T cells emerge early in circulation after gene therapy for SCID-X1 [Bisulfite-Seq]

ABSTRACT: Memory-like T cells emerge early in circulation after gene therapy for SCID-X1 [Bisulfite-Seq]

PROVIDER: PRJNA1280811 | ENA |

REPOSITORIES: ENA

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Memory-like T cells emerge early in circulation after gene therapy for SCID-X1 [Bisulfite-Seq]

Project description:Studying the emerging immune system after successful gene therapy for X-linked severe combined immunodeficiency (SCID-X1) in infants provides a unique opportunity to characterize human T cell development. Here we report our longitudinal analysis of T cells isolated from the peripheral blood of SCID-X1 patients after treatment with gene-transduced autologous CD34+ cells. We observed an early enrichment of memory-like T cells, which was intriguing given that newly generated T cells were unlikely to have previously encountered their cognate antigen. Single-cell RNA sequencing of the emerging and established T cell pool identified a subset of memory-like cells enriched for NKG2A expression that contained innate-associated transcriptional profiles. Genome-wide epigenetic profiling of the de novo memory-like NKG2A+ T cell subset confirmed an epigenetic permissivity of this locus along with programs indicating a poised effector response. Consistent with the epigenetic profile, ex vivo stimulation of NKG2A+ T cells with IL-12 and IL-18 resulted in antigen-independent IFNg expression. Collectively, these data suggest that NKG2A+ innate memory-like T cells develop early in human life and are epigenetically poised to rapidly elicit effector cytokines in an antigen-independent manner.

2025-07-31 | GSE300395 | GEO

Memory-like T cells emerge early in circulation after gene therapy for SCID-X1 [scRNA-seq]

Project description:Memory-like T cells emerge early in circulation after gene therapy for SCID-X1 [scRNA-seq]

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Integrome signatures of lentiviral gene therapy for SCID-X1 patients

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Integrome signatures of lentiviral gene therapy for SCID-X1 patients

Project description:Integrome signatures of lentiviral gene therapy for SCID-X1 patients

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Integrome signatures of lentiviral gene therapy for SCID-X1 patients

Project description:Lentiviral vector (LV)-based gene therapy holds promise for a broad range of diseases. Analyzing more than 280,000 vector integration sites (VISs) in 273 samples from 10 patients with X-linked severe combined immunodeficiency (SCID-X1), we discovered shared LV integrome signatures in 9 out of 10 patients in relation to the genomics, epigenomics, and 3D structure of the human genome. VISs were enriched in the nuclear sub-compartment A1 and integrated into super-enhancers close to nuclear pore complexes. These signatures were validated in T cells transduced with an LV encoding a CD19-specific chimeric antigen receptor. Intriguingly, the one patient whose VISs deviated from the identified integrome signatures had a distinct clinical course. Comparison of LV and gamma retrovirus integromes regarding their 3D genome signatures, identified differences that might explain the lower risk of insertional mutagenesis in LV-based gene therapy. Our findings suggest that LV integrome signatures, shaped by common features such as genome organization, may impact the efficacy of LV-based cellular therapies.

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