Aging compromises terminal differentiation program of cytotoxic effector lineage and promotes exhaustion in CD8+ T cells responding to coronavirus infection [scRNA-seq]
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ABSTRACT:
PROVIDER: PRJNA1198068 | ENA |
REPOSITORIES: ENA
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Project description:T cell aging increases the risk of viral infection-related morbidity and mortality and reduces vaccine efficacy in the elderly. A major hallmark of T cell aging is the loss of quiescence and shift towards terminal differentiation during homeostasis. However, how aging alters the differentiation program of virus-specific T cells during infection is unclear. Here, in a murine coronavirus (MHV) infection model with age-associated increased mortality, we demonstrate that aging impairs, instead of promoting, the terminal differentiation program of virus-specific CD8+ T cells. Upon infection, CD8+ and CD4+ T cells in old mice showed marked reduction in clonal expansion and upregulation of immune checkpoints associated with T cell exhaustion. Bulk and single-cell transcriptomics showed that aging upregulated T cell exhaustion transcriptional program associated with TOX in virus-specific CD8+ T cells and shift the myeloid compartment from immunostimulatory to immunosuppressive phenotype. In addition, aging downregulated the transcriptional program of terminally differentiated effector CD8+ T cells and diminished CX3CR1+ cytotoxic effector lineage. Mechanistically, virus-specific CD8+ T cells from infected aged mice displayed defects in inducing transcription factors ZEB2 and KLF2, which were required for terminal differentiation of effector CD8+ T cells. Together, our study shows that aging impairs terminal differentiation and promotes exhaustion of virus-specific CD8+ T cells responding to coronavirus infection through dysregulating expression of lineage-defining transcription factors.
2025-08-20 | GSE284244 | GEO
Project description:T cell aging increases the risk of viral infection-related morbidity and mortality and reduces vaccine efficacy in the elderly. A major hallmark of T cell aging is the loss of quiescence and shift towards terminal differentiation during homeostasis. However, how aging alters the differentiation program of virus-specific T cells during infection is unclear. Here, in a murine coronavirus (MHV) infection model with age-associated increased mortality, we demonstrate that aging impairs, instead of promoting, the terminal differentiation program of virus-specific CD8+ T cells. Upon infection, CD8+ and CD4+ T cells in old mice showed marked reduction in clonal expansion and upregulation of immune checkpoints associated with T cell exhaustion. Bulk and single-cell transcriptomics showed that aging upregulated T cell exhaustion transcriptional program associated with TOX in virus-specific CD8+ T cells and shift the myeloid compartment from immunostimulatory to immunosuppressive phenotype. In addition, aging downregulated the transcriptional program of terminally differentiated effector CD8+ T cells and diminished CX3CR1+ cytotoxic effector lineage. Mechanistically, virus-specific CD8+ T cells from infected aged mice displayed defects in inducing transcription factors ZEB2 and KLF2, which were required for terminal differentiation of effector CD8+ T cells. Together, our study shows that aging impairs terminal differentiation and promotes exhaustion of virus-specific CD8+ T cells responding to coronavirus infection through dysregulating expression of lineage-defining transcription factors.
2025-08-20 | GSE284243 | GEO
Project description:Aging compromises terminal differentiation program of cytotoxic effector lineage and promotes exhaustion in CD8+ T cells responding to coronavirus infection [RNA-seq]
| PRJNA1198063 | ENA
Project description:Prolonged exposure to antigens drives CD8+ cytotoxic T lymphocytes (CTLs) to a hypofunctional state known as exhaustion, which compromises their ability to control infections and cancer. Here, we identify O-GlcNAcylation (O-GlcNAc)—a nutrient-sensitive post-translational modification—as a critical regulator for CTL exhaustion. Exhausted CTLs elevated nucleus O-GlcNAc levels, coupled with increased levels of the cellular uridine diphosphate GlcNAc (UDP-GlcNAc) relative to their effector counterparts. Using quantitative chemoenzymatic O-GlcNAcomic analysis, we identified a T-box transcription factor downstream of TCF-1-centered exhaustion transition and sustenance, eomesodermin (Eomes), which undergoes intensive O-GlcNAcylation. Mechanistically, mutation of the primary O-GlcNAc sites on Eomes abolished its glycosylation, but their phosphorylation and interactions with O-GlcNAc transferase (OGT) were unaffected. OGT/Eomes was indispensable for interaction with TCF-1. OGT stabilized Eomes and increased its accumulation in the nucleus, where T-bet-to-Eomes transcriptional transition drives functional exhaustion. These results uncover a novel regulatory relationship between OGT and the TCF-1/Eomes axis in promoting CTL exhaustion and impairing their protective function.
2025-07-01 | GSE298788 | GEO
Project description:Exhaustion-associated cholesterol deficiency dampens the cytotoxic arm of antitumor immunity
| PRJNA955168 | ENA
Project description:The concept of targeting cholesterol metabolism to treat cancer has been widely tested in clinics but the benefits are modest, calling for a complete understanding of cholesterol metabolism of intratumoral cells. Low cholesterol levels inhibit T-cell proliferation and cause autophagy mediated apoptosis, particularly for cytotoxic T cells. In the tumor microenvironment, oxysterols mediate reciprocal alterations of the LXR and SREBP2 pathways to cause cholesterol deficiency of T cells, subsequently leading to aberrant metabolic and signaling pathways that drive T cell exhaustion/dysfunction. LXR depletion in CAR-T cells led to improved antitumor function against solid tumor.
2023-04-13 | GSE229611 | GEO
Project description:O-GlcNAc Transferase Promotes Eomesodermin-mediated Exhaustion of CD8+ Cytotoxic T Lymphocytes
| PRJNA1271106 | ENA
Project description:CD4+ conventional T (Tconv) lymphocytes display an important role in tumor immunity; however, their contribution to tumor elimination remains poorly understood. Here we describe a subset of tumor-infiltrating Tconv cells characterized by the expression of CD39. In mouse cancer models CD39+ Tconv cells accumulate with tumor growth but are absent in lymphoid organs. Compared to tumor CD39- Tconv cells, CD39+ cells exhibit a cytotoxic and exhausted signature at the transcriptomic level, confirmed by high protein expression of co-inhibitory receptors and transcription factors related to exhaustion. Additionally, CD39+ Tconv cells show an increased production of INFg, Granzyme B, Perforin and CD107a, but a reduced production of TNF upon in vitro stimulation. In vivo, CTLA-4 blockage induces the expansion of CD39+ Tconv cells in the tumor, while maintaining their features of cytotoxicity and exhaustion. In breast cancer patients, CD39+ Tconv cells are found in tumors, and at lower frequency in the adjacent non-tumoral mammary tissue. CD39+ Tconv cells are also present in metastatic but not detected in non-metastatic lymph nodes and blood. Human tumor CD39+ Tconv cells constitute a heterogeneous cell population with features of exhaustion, impaired TNF production, and high expression of co-inhibitory receptors and CD107a. High gene expression of CD4 and ENTPD1 (CD39) in human tumor tissues correlates with higher overall survival rate in breast cancer patients. Our results identify CD39 as a biomarker of CD4+ T cells with characteristics of both exhaustion and cytotoxic potential and put forward CD39+ Tconv cells as pivotal players of the immune response against tumors.
2024-01-01 | GSE221881 | GEO
Project description:The failure of T-cells to control tumor growth has been associated with several functional defects that collectively lead to T-cell “exhaustion.” This phenotype results from chronic antigen stimulation within the tumor microenvironment, but how repetitive antigenic stimulation leads to T-cell exhaustion remains poorly defined. Here we show that persistent antigen stimulation induces mitochondrial oxidative stress that reduces tricarboxylic acid (TCA) cycle activity. The resultant bioenergetic compromise impairs nucleotide triphosphate synthesis, induces endoplasmic reticulum (ER) stress, and activates an exhaustion-associated gene expression program. Reversal of oxidative stress with N-acetylcysteine effectively restores T-cell proliferation, effector function, and memory-associated gene expression and enhances anti-tumor T-cell efficacy in vivo. These data reveal that induction of mitochondrial oxidative stress is a critical component of terminal T-cell dysfunction. Furthermore, treatments that restore mitochondrial redox are sufficient to prevent T-cell exhaustion and enhance anti-tumor immunity.
2020-05-21 | GSE138459 | GEO
Project description:While terminally exhausted T cells (Tex_term) retain important anti-tumor cytotoxic function, it is the relative preservation of renewable, stem-like progenitor exhaustion (Tex_prog) that better indicates immunotherapeutic responsivity. Although restraining the progression from Tex_prog to Tex_term thus takes on clinical significance, the cellular interactions in a tumor microenvironment (TME) governing such progression remain less established. Employing glioblastoma (GBM) and other solid tumors as models of severe exhaustion, we provide a detailed characterization of the progression from Tex_prog to Tex_term within the TME, where we observe a striking and disproportionate loss of Tex_prog over time, leading to a low progenitor exhaustion to terminal exhaustion ratio (PETER). We find exhaustion concentrated within tumor-specific T cell subsets, with cognate antigenic exposure requisite for acquisition of the Tex_term phenotype. However, we implicate tumor-associated macrophages (TAM), and not tumor cells, as the source of antigenic exposure governing the Tex_prog to Tex_term transition. Using cell – cell interaction analysis, we additionally highlight candidate receptor–ligand communications that may be specifically mediating the progression to Tex_term and resultant decline in PETER within the TME.
2024-02-01 | GSE236243 | GEO