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Translational Downregulation of 5’ TOP mRNAs During T Cell Exhaustion [Ribo-Seq]

ABSTRACT: T cell exhaustion is a dysfunctional state that arises during chronic infections and cancer, characterized by impaired effector functions and sustained expression of inhibitory receptors. While transcriptional, epigenetic, and metabolic rewiring have been well documented in exhausted T cells, a comprehensive understanding of how translation is regulated in this state remains incomplete. To address this gap, we performed ribosome profiling and RNA sequencing on exhausted human CD8⁺ T cells to globally assess translational control. Our analyses reveal a marked repression of 5’ terminal oligopyrimidine (TOP) mRNAs during exhaustion. Unexpectedly, we demonstrate that this translational repression occurs despite evidence of elevated mTOR activity in exhausted T cells. These findings uncover a previously unknown layer of translational control in exhausted T cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE313692 | GEO | 2025/12/18

REPOSITORIES: GEO

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Translational Downregulation of 5’ TOP mRNAs During T Cell Exhaustion [RNA-Seq]

Project description:T cell exhaustion is a dysfunctional state that arises during chronic infections and cancer, characterized by impaired effector functions and sustained expression of inhibitory receptors. While transcriptional, epigenetic, and metabolic rewiring have been well documented in exhausted T cells, a comprehensive understanding of how translation is regulated in this state remains incomplete. To address this gap, we performed ribosome profiling and RNA sequencing on exhausted human CD8⁺ T cells to globally assess translational control. Our analyses reveal a marked repression of 5’ terminal oligopyrimidine (TOP) mRNAs during exhaustion. Unexpectedly, we demonstrate that this translational repression occurs despite evidence of elevated mTOR activity in exhausted T cells. These findings uncover a previously unknown layer of translational control in exhausted T cells.

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Translational Downregulation of 5’ TOP mRNAs During T Cell Exhaustion [Ribo-Seq]

Project description:Translational Downregulation of 5’ TOP mRNAs During T Cell Exhaustion [Ribo-Seq]

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PD-L1 overexpression, SWI/SNF complex Deregulation and Profound Transcriptomic Changes Characterize Cancer-Dependent Exhaustion of Persistently Activated CD4+ T Cells

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Project description:Persistent exposure to antigen during chronic infection or cancer renders T cells dysfunctional. The molecular mechanisms regulating this state of exhaustion are thought to be common in infection and cancer, despite obvious differences in their microenvironments. We discovered that NFAT5, an NFAT family member lacking an AP-1 docking site, is highly expressed in exhausted T cells responding to chronic infection and tumors but is a central player selectively in tumor-induced exhaustion. While NFAT5 overexpression in CD8+ T cells reduced tumor control, NFAT5 deletion improved tumor control by promoting the accumulation of tumor-specific CD8 T cells that expressed less TOX and PD-1 and produced more cytokines specifically among precursor exhausted cells. Conversely, NFAT5 did not promote T cell exhaustion during chronic infection. While NFAT5 expression was induced by TCR triggering, its transcriptional activity was specific to the tumor microenvironment and required hyperosmolarity. NFAT5 thus promotes CD8 T cell exhaustion in a tumor-selective fashion.

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NFAT5 induction by the tumor microenvironment enforces CD8 T cell exhaustion (CUT&Tag)

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O-GlcNAc Transferase Promotes Eomesodermin-mediated Exhaustion of CD8+ Cytotoxic T Lymphocytes

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

Contrasting functions of CD73 and adenosine in CD8+ T cell exhaustion

Project description:T cell exhaustion is a state of functional decline in T cells, driven by chronic antigen exposure and inhibitory signals within the tumor microenvironment. Exhausted CD8+ T cells (Tex) derive from precursor exhausted T cells (Tpex), a self-renewing population responsible for the proliferative burst observed in anti-PD-1 therapies. Exhausted cells are exposed to adenosine in the tumor, yet the role of the CD73/adenosine axis and Tpex/Tex differentiation remains unclear. Using an in vitro model for CD8+ T cell exhaustion, we found that CD73 expression increased during Tpex formation and that its expression is negatively correlated with Tex generation. CD73-deficient (CD73KO) CD8⁺ T cells showed impaired activation and reduced progression to Tex. Moreover, we demonstrated that CD73 promotes transcriptional expression of the adenosine receptor A2A (A2AR) and the differentiation into IFNγ/TNFα-producing Tex cells. RNAseq analysis of exhausted CD73KO CD8+ T cells showed a more stem-like transcriptomic profile and enrichment in genes associated with the immune response than their WT counterpart. In vivo, co-transfer of naïve CD73 KO and WT tumor antigen-specific CD8⁺ T cells into tumor-bearing mice showed increased Tpex frequency and numbers among CD73KO cells in tumors. Conversely, in vitro exhaustion in the presence of A2AR agonists decreased Tex frequency and activation/exhaustion markers, while increasing CD73 and CD62L, markers associated with stemness. Supporting this, A2AR blockade with SYN115 in tumor-bearing mice reduced Tpex markers and increased Tex differentiation. Altogether, our data suggest CD73 promotes Tpex-to-Tex differentiation, whereas adenosine-A2AR signaling supports Tpex maintenance in the tumor microenvironment.

2025-05-30 | GSE298159 | GEO

Thrombospondin-1:CD47 signaling contributes to the development of T cell exhaustion in cancer.

Project description:T cell exhaustion, a hyporesponsive state of antigen-specific CD8+ T cells exhibiting elevated expression of multiple inhibitory surface receptors, is a major obstacle for the treatment of cancer. Current immune checkpoint blockade (ICB) therapies aimed at reinvigorating exhausted CD8+ T cells have demonstrated clinical effectiveness. However, not all cancer patients achieve long-term disease control due, at least in part, to the refractory nature of terminally exhausted CD8+ T cells to be functionally reinvigorated. Besides persistent antigen stimulation, the environmental sources and mechanisms that lead to CD8+ T cell exhaustion in cancer remain to be thoroughly characterized. Here, we show that the expression of CD47 [a.k.a. integrin-associated protein (IAP) and ‘‘don’t eat me’’ signal is upregulated in tumour-associated, exhausted CD8+ T cell compartments in both human and murine tumours. Our findings reveal a novel role of the extracellular matrix protein thrombospondin-1 (TSP-1) and CD47 in promoting T cell exhaustion. Engagement of TSP-1 with CD47 drives the upregulation of TOX and inhibitory immune checkpoint molecules and compromises the effector function of CD8+ T cells during tumour progression. Mechanistically, the interaction of TSP-1 with CD47 on CD+ T cells activates the calcineurin-NFAT signaling, thereby promoting TOX expression and the T cell exhaustion program in cancer.

2025-09-17 | GSE303017 | GEO

The global downregulation of protein synthesis observed during hepatogenic maturation is associated with a decrease in TOP mRNA translation

Project description:Translational regulation is of paramount importance for proteome remodeling during stem cell differentiation both at the global and transcript-specific level. In this study, we characterized translational remodeling during hepatogenic differentiation of induced pluripotent stem cells (iPSCs) by polysome profiling. We demonstrate that protein synthesis increases during the initial exit from pluripotency, but is then globally repressed during later steps of hepatogenic maturation. This global downregulation of translation is accompanied by a decrease in the protein abundance of components of the translation machinery, which involves a global reduction in translational efficiency of terminal oligopyrimidine tract (TOP) mRNA encoding translation-related factors. Despite global translational repression during hepatogenic differentiation, key hepatogenic genes remain efficiently translated, and the translation of several transcripts involved in hepato-specific functions and metabolic maturation are even induced. We conclude that, during hepatogenic differentiation, a global decrease in protein synthesis is accompanied by a specific translational rewiring towards hepato-specific transcripts.

2021-04-23 | GSE173106 | GEO

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