Translational repression of pre-formed cytokine-encoding mRNA prevents chronic activation of memory T cells

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Background:

• Memory T cells are crucial for rapid responses to infections.
• These cells maintain a pool of cytokine-encoding messenger RNAs (mRNAs) for quick protein synthesis.
• Mechanisms preventing premature protein production from these stored mRNAs are not fully understood.

Purpose of the Study:

• To investigate how protein translation from pre-formed cytokine mRNAs is repressed in memory T cells without infection.
• To identify the regulatory elements and factors involved in this translational control.

Main Methods:

• Utilized germline deletion of AU-rich elements (AREs) in the Interferon-gamma (Ifng) 3' untranslated region (3' UTR) in mouse models.
• Assessed cytokine production and mRNA translation efficiency in memory T cells.
• Investigated the role of the ARE-binding protein ZFP36L2 in translational repression.

Main Results:

• Deletion of AREs in the Ifng 3' UTR resulted in chronic cytokine production in memory T cells.
• This aberrant protein production was not due to increased mRNA levels or stability.
• AREs were found to block the recruitment of cytokine mRNA to ribosomes, a process dependent on ZFP36L2.

Conclusions:

• AU-rich elements (AREs) in the 3' untranslated region (3' UTR) mediate translational repression in memory T cells.
• This mechanism prevents undesirable protein production from cytokine mRNAs in the absence of infection.
• The ARE-binding protein ZFP36L2 is essential for this translational block in both mouse and human memory T cells.