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Updated: Jan 7, 2026
Measuring Mitochondrial Function of Naïve and Effector CD8 T Cells
Published on: March 28, 2025
Translational Downregulation of 5' TOP mRNAs During T Cell Exhaustion
Erica S Pledger1,2, Navya Ambavaram1,2, Lucas Ferguson1
1Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, CA, USA.
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.
Insights
T cell exhaustion involves impaired function during chronic disease. This study reveals that translation of specific mRNAs is repressed in exhausted T cells, despite increased mTOR activity, uncovering a new regulatory mechanism.
Area of Science:
- Immunology
- Molecular Biology
- Cancer Research
Background:
- T cell exhaustion impairs immune responses in chronic infections and cancer.
- Known rewiring includes transcriptional, epigenetic, and metabolic changes.
- Translational regulation in exhausted T cells is not fully understood.
Purpose of the Study:
- To investigate translational control mechanisms in exhausted human CD8+ T cells.
- To identify specific mRNA targets regulated at the translational level during T cell exhaustion.
Main Methods:
- Ribosome profiling and RNA sequencing were performed on exhausted human CD8+ T cells.
- Global assessment of translational control was conducted.
Main Results:
- A significant repression of 5' terminal oligopyrimidine (TOP) mRNAs was observed in exhausted T cells.
- This translational repression occurred independently of mTOR activity levels, which were found to be elevated.
Conclusions:
- A novel layer of translational control exists in exhausted T cells.
- Repression of TOP mRNAs represents a key feature of T cell exhaustion.
- Findings challenge existing models of translational regulation in exhausted T cells.
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