RNA-seq analysis of human peripheral blood Treg cells stratified into four equal fractions according to CD38 intensity
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE325333 | GEO | 2026/05/15
REPOSITORIES: GEO
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Project description:CD38, an ecto-enzyme involved in NAD+ catabolism, is highly expressed in exhausted CD8+ T cells and has emerged as an attractive target to improve response to immune checkpoint blockade (ICB) by blunting T cell exhaustion. However, the precise role(s) and regulation of CD38 in exhausted T cells and the efficacy of CD38-directed therapeutic strategies in human cancer remain incompletely defined. Here, we show that CD38+CD8+ T cells are induced by chronic TCR activation and type I interferon stimulation and confirm their association with ICB resistance in human melanoma. Disrupting CD38 restores cellular NAD+ pools and improves T cell bioenergetics and effector functions. Targeting CD38 restores ICB sensitivity in a cohort of patient-derived organotypic tumor spheroids from explanted melanoma specimens. These results support further preclinical and clinical evaluation of CD38-directed therapies in melanoma and underscore the importance of NAD+ as a vital metabolite to enhance those therapies.
2025-05-14 | GSE296471 | GEO
Project description:CD38, an ecto-enzyme involved in NAD+ catabolism, is highly expressed in exhausted CD8+ T cells and has emerged as an attractive target to improve response to immune checkpoint blockade (ICB) by blunting T cell exhaustion. However, the precise role(s) and regulation of CD38 in exhausted T cells and the efficacy of CD38-directed therapeutic strategies in human cancer remain incompletely defined. Here, we show that CD38+CD8+ T cells are induced by chronic TCR activation and type I interferon stimulation and confirm their association with ICB resistance in human melanoma. Disrupting CD38 restores cellular NAD+ pools and improves T cell bioenergetics and effector functions. Targeting CD38 restores ICB sensitivity in a cohort of patient-derived organotypic tumor spheroids from explanted melanoma specimens. These results support further preclinical and clinical evaluation of CD38-directed therapies in melanoma and underscore the importance of NAD+ as a vital metabolite to enhance those therapies.
2025-05-14 | GSE296926 | GEO
Project description:CD38 is an ectoenzyme that converts NAD+ to NAM and helps to maintain bioenergetic homeostasis. A better understanding of CD38 biology in the brain is needed, considering the evidence for CD38 dysregulation and/or gene variation in neurodegenerative conditions such as Parkinson’s Disease (PD) and Alzheimer’s Disease (AD). Here, we demonstrate enrichment of Cd38 in midbrain astrocytes and describe how CD38 deficiency influences brain metabolism, astrocytic gene expression, and bioenergetics. We demonstrate increased NAD content, decreased NAM content, and increased NAD/NAM in the midbrain and striatum of CD38-deficient (Cd38-/-) mice, indicating the dependence on CD38 for NAD to NAM conversion. RNA-sequencing of isolated astrocytes revealed numerous differentially expressed genes in Cd38+/- and Cd38-/- mice, with alterations in mitochondrial, metabolic, and senescence-related genes and several genes involved in PD and AD etiology. Interestingly, Seahorse XFe24 mitochondrial functional evaluation in primary astrocyte cultures from Cd38+/+, Cd38+/-, and Cd38-/- mice revealed enhanced oxygen consumption, with an increase in glycolytic rate with Cd38 deficiency. These findings indicate a novel role for astrocytes in the regulation of CD38-dependent NAD/NAM homeostasis in the brain and provide the framework for future studies evaluating the relationship between CD38 dysfunction, aging, and vulnerability of neuronal populations in neurodegenerative disease. Also, these studies highlight the need to better elucidate the impact of CD38 deficiency on brain metabolism, considering ongoing clinical trials using CD38 inhibitors for the treatment of multiple myeloma and other cancers.
2025-12-30 | GSE272765 | GEO
Project description:Nicotinamide adenine dinucleotide (NAD+) is a critical metabolic co-enzyme which is strongly implicated in the pathogenesis of brain aging and neurodegenerative diseases. Prevention of age-related decline in brain NAD+ levels is an attractive therapeutic strategy for combating age-related neurodegeneration, emphasizing the need to fully understand molecular mechanisms regulating brain NAD+ levels. Previous work has shown that the circadian protein REV-ERBα regulates cellular NAD+ levels in cardiac tissue via control of the NAD+ producing enzyme NAMPT. Whether this pathway regulates brain NAD+ levels, however, is unknown. Here, we show that REV-ERBα controls brain NAD+ levels through a distinct pathway involving suppression of the NAD+ consuming enzyme CD38 in astrocytes. Under basal conditions, REV-ERBα suppresses the transcription factor NFIL3 (E4BP4) which itself provides tonic inhibition of CD38 expression, elevating CD38 levels and keeping NAD+ levels low. Deletion of REV-ERBα, either globally or specifically in astrocytes, led to induction of NFIL3, suppression of CD38, increased NAD+, and mitigated protein aggregation, inflammation, and neurodegeneration in a mouse model of tauopathy. This pathway appears to be unique to the brain, as REV-ERBα deletion does not affect NAMPT expression in the brain, does not suppress CD38 in the liver, and has an opposite effect on NAD+ levels in the brain as in the heart. Our data show that the circadian nuclear receptor REV-ERBα can regulate NAD+ via distinct mechanisms in different tissues and define a REV-ERBα-NFIL3-NAD+ downstream pathway controlling brain NAD+ metabolism and neurodegeneration.
2025-06-27 | GSE255975 | GEO
Project description:CD38, a multi-functional membrane receptor and enzyme, consumes NAD+ to generate products such as cyclic-ADP-ribose. CD38 knockout mice show elevated tissue and blood NAD+ level. Chronic feeding of high-fat, high-sucrose diet to wild type mice leads to exercise intolerance and reduced metabolic flexibility. Loss of CD38 by genetic mutation protects mice from diet-induced metabolic deficit. These animal model results suggest that elevation of tissue NAD+ through genetic ablation of CD38 can profoundly alter energy homeostasis in animals that are maintained on a calorically-excessive Western diet.
2015-05-20 | GSE69062 | GEO
Project description:Objectives: In gout, flares of severely painful inflammatory arthritis intersect with metabolism, circadian rhythm, and macrophage activation. NAD+ is a necessary cofactor and key metabolite in cellular bioenergy homeostasis, and NAD+ suppresses the NLRP3 inflammasome and inflammation. However, cellular NAD+ declines in inflammatory states, associated with increased activity of the leukocyte-expressed NADase CD38. Gouty arthritis is principally prevented and treated with nonselective and frequently toxic drugs (colchicine, NSAIDs, corticosteroids). Hence, we tested the potential role of therapeutically targeting CD38 and NAD+ in gout. Methods: We studied cultured mouse wild type and CD38 knockout (KO) murine bone marrow derived macrophages (BMDMs) stimulated by monosodium urate (MSU) crystals, and the air pouch gout synovitis model. Results: MSU crystals induced CD38 in BMDMs in vitro, associated with NAD+ depletion, and IL-1b and CXCL1 release, effects reversed by pharmacologic CD38 inhibitors (apigenin, 78c). Mouse air pouch inflammatory responses to MSU crystals were blunted by CD38 KO and apigenin. Pharmacologic CD38 inhibition suppressed MSU crystal-induced NLRP3 inflammasome activation and increased anti-inflammatory SIRT3-SOD2 in macrophages. BMDM RNA-seq analysis of 176 differentially expressed genes (DEGs) revealed CD38 control of multiple MSU crystal-modulated inflammation pathways. The top DEGs included the circadian rhythm modulator GRP176, and the metalloreductase STEAP4 that mediates iron homeostasis, and promotes oxidative stress and NF-kB activation when it is overexpressed. Conclusion: CD38 and NAD+ depletion are druggable targets controlling the MSU crystal- induced inflammation program. Targeting CD38 and NAD+ are potentially novel selective molecular approaches to limit gouty arthritis.
2024-05-08 | GSE214587 | GEO
Project description:Mammalian female reproductive lifespan is typically significantly shorter than life expectancy and is associated with a decrease in ovarian NAD levels. However, the mechanisms underlying this loss of ovarian NAD are unclear. Here, we show that CD38, a NAD consuming enzyme, is expressed in the ovarian extrafollicular space, primarily in immune cells, and its levels increase with reproductive age. Reproductively young mice lacking CD38 exhibit larger primordial follicle pools, elevated ovarian NAD levels, and increased fecundity relative to wild type controls. This larger ovarian reserve results from a prolonged window of follicle formation during early development. However, the beneficial effect of CD38 loss on reproductive function is not maintained at advanced age. Our results demonstrate a novel role of CD38 in regulating ovarian NAD metabolism and establishing the ovarian reserve, a critical process that dictates a female reproductive lifespan.
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Project description:Decline in tissue NAD levels during aging has been linked to aging-associated diseases, such as age-related metabolic disease, physical decline, and Alzheimers disease. However, the mechanism for aging-associated NAD decline remains unclear. Here we report that pro-inflammatory M1 macrophages, but not naive or M2 macrophages, highly express the NAD consuming enzyme CD38 and have enhanced CD38-dependent NADase activity. Furthermore, we show that aging is associated with enhanced inflammation due to increased senescent cells, and the accumulation of CD38 positive M1 macrophages in visceral white adipose tissue. We also find that inflammatory cytokines found in the supernatant from senescent cells (Senescence associated secretory proteins, SASP) induces macrophages to proliferate and express CD38. As senescent cells progressively accumulate in adipose tissue during aging, these results highlight a new causal link between visceral tissue senescence and tissue NAD decline during aging and may present a novel therapeutic opportunity to maintain NAD levels during aging.
2019-04-25 | MSV000083726 | MassIVE
Project description:Neonatal life is marked by rapid antigen exposure, necessitating establishment of peripheral immune tolerance via conversion of naïve CD4+ T cells into regulatory T cells (Tregs). Here, we demonstrate that increased Treg differentiation by naive CD4+ T cells from human cord blood versus adult blood is integrally linked to their unique metabolic profile and their elevated expression of the NADase, CD38. Early life naïve CD4+ T cells demonstrate a metabolic preference for glycolysis, which directly facilitates their Treg generation. We reveal an age-dependent gradient in CD38 levels on naïve CD4+ T cells and show that high CD38 expression contributes to both the glycolytic state and high Treg potential of neonatal CD4+ T cells, effects that are mediated at least in part via the NAD-dependent deacetylase SIRT1. Thus, the early life window for peripheral tolerance in humans is critically enabled by the immunometabolic state of the naïve CD4+ compartment.
2026-02-12 | GSE282496 | GEO
Project description:Mediator of IRF3 activation (MITA, also known as STING) is a cyclic GMP-AMP (cGAMP) receptor that activates type I interferon responses to inhibit tumorigenesis in tumor cells. However, the MITA agonists have limited antitumor efficacy in clinical trials. Here we show that MITA in macrophages promotes the survival of regulatory T cell (Treg) in the tumor microenvironment (TME) and the progression of non-small cell lung cancer (NSCLC) in the KRasG12D autochthonous NSCLC mouse models. Mechanistically, MITA-mediated activation of NF-B upregulates CD38 in monocyte-derived macrophages (MDMs) that metabolizes nicotinamide adenine dinucleotide (NAD) into niacinamide (NAM) and ADP-ribose in the TME. Inhibition of CD38 enzymatic activity or deletion of MITA or CD38 alone or simultaneously in macrophages results in the accumulation of NAD that induces apoptosis of Treg via the ART2-P2RX7 axis and enhances antitumor CD8+ T-cell responses in the TME. Importantly, pharmacological inhibition of CD38 sensitizes mice to the low-dose anti-CTLA4 therapy in the KRasG12D autochthonous NSCLC mouse models. These findings uncover a previously uncharacterized cGAMP-MITA-CD38 axis in MDMs that supports Treg survival and NSCLC progression and highlight potential therapeutic strategies for immune checkpoint blockade (ICB)-resistant cancers.
2025-11-29 | GSE288401 | GEO