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CTLA-4-mediated posttranslational modifications direct cytotoxic T-lymphocyte differentiation
Holger Lingel1, Josef Wissing2, Aditya Arra1
1Department of Experimental Pediatrics, University Hospital, Health Campus Immunology, Infectiology and Inflammation, Otto-von-Guericke-University, Magdeburg 39120, Germany.
Abstract:
The blockade of inhibitory receptors such as CTLA-4 (CD152) is being used as immune-checkpoint therapy, offering a powerful strategy to restore effective immune responses against tumors. To determine signal components that are induced under the control of CTLA-4 we analyzed activated murine CD8+ T cells by quantitative proteomics. Accurate mass spectrometry revealed that CTLA-4 engagement led to central changes in the phosphorylation of proteins involved in T-cell differentiation. Beside other targets, we discovered a CTLA-4-mediated induction of the translational inhibitor programmed cell death-4 (PDCD4) as a result of FoxO1 nuclear re-localization. PDCD4 further bound a distinct set of mRNAs including Glutaminase, which points out a critical role for CTLA-4 in CD8+ T-cell metabolism. Consequently, PDCD4-deficient cytotoxic T-lymphocytes (CTLs) expressed increased amounts of otherwise repressed effector molecules and ultimately led to superior control of tumor growth in vivo. These findings reveal a novel CTLA-4-mediated pathway to attenuate CTLs and indicate the importance of post-transcriptional mechanisms in the regulation of anti-tumor immune responses.
Insights
Blocking CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) restores anti-tumor immunity. CTLA-4 induces PDCD4 (programmed cell death-4), which suppresses T-cell function and metabolism, impacting tumor control.
Area of Science:
- Immunology
- Molecular Biology
- Cancer Research
Background:
- Immune-checkpoint therapy using CTLA-4 blockade enhances anti-tumor immune responses.
- Understanding CTLA-4 signaling is crucial for optimizing cancer immunotherapy.
Purpose of the Study:
- To identify signaling components regulated by CTLA-4 in activated CD8+ T cells.
- To elucidate the role of CTLA-4 in regulating T-cell function and metabolism.
Main Methods:
- Quantitative proteomics and mass spectrometry on activated murine CD8+ T cells.
- Analysis of protein phosphorylation and mRNA binding.
- Assessment of PDCD4-deficient cytotoxic T-lymphocytes (CTLs) in vivo tumor models.
Main Results:
- CTLA-4 engagement induces changes in T-cell differentiation-related protein phosphorylation.
- CTLA-4 mediates the induction of programmed cell death-4 (PDCD4) via FoxO1 re-localization.
- PDCD4 regulates T-cell metabolism by binding mRNAs like Glutaminase, and its deficiency enhances CTL effector function and tumor control.
Conclusions:
- A novel CTLA-4 pathway involving PDCD4 attenuates CTL function and impacts anti-tumor immunity.
- Post-transcriptional mechanisms play a critical role in regulating anti-tumor immune responses.
- Targeting CTLA-4 and its downstream effectors may improve cancer immunotherapy efficacy.
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