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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE300394 | GEO | 2025/07/31

REPOSITORIES: GEO

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Project description:Immune memory cells are poised to rapidly expand and elaborate effector functions upon reinfection. However, despite heightened readiness to respond, memory cells exist in a functionally quiescent state. The paradigm is that memory cells remain inactive due to lack of TCR stimuli. Here we report a unique role of Tregs in orchestrating memory quiescence by inhibiting effector and proliferation programs through CTLA-4. Loss of Tregs resulted in activation of genome-wide transcriptional programs characteristic of potent effectors, and both developing and established memory quickly reverted to a terminally differentiated (KLRG-1hi/IL-7R±lo/GzmBhi) phenotype, with compromised metabolic fitness, longevity, polyfunctionality and protective efficacy. CTLA-4, an inhibitory receptor overexpressed on Tregs, functionally replaced Tregs in trans to rescue Treg-less memory defects and restore homeostasis of secondary mediators as well. These studies present CD28-CTLA-4-CD80/CD86 axis as a novel target to potentially accelerate vaccine-induced immunity and improve T-cell memory quality in current cancer immunotherapies proposing transient Treg-depletion. We used microarray analysis to detail the global programming of gene expression in LCMV GP33-specific CD8 T cells differentiated in the presence or absence of regulatory T cells Differentiation of memory CD8 T cells entails a progressive transition of highly activated effector program to a quiescent memory program. A key question in the field is to understand the factors that aid in the differentiation of memory cells from effector cells. It is a generally accepted paradigm that effector cells transition to a memory state by default after antigen clearance, since TCR stimuli is the key driver of effector programs in CD8 T cells. We hypothesized that the effector to memory transition of CD8 T cells involves active immunological brakes through regulatory T cells (Tregs) that allow the highly activated effector cells to convert into quiescent memory cells. To address this hypothesis, we used FoxP3-DTR mice to deplete Tregs during the window following antigen clearance, during which the effector CD8 T cells convert to long-lived memory cells. To get a deeper understanding of the global transcriptome of CD8 T cells as they transition from an effector to a memory state, we isolated and arrayed the antigen-specific CD8 T cells at day 16 post-infection that have experienced the transitional environment with and without the presence of Tregs.

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

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