BCOR and ZC3H12A suppress a core stemness program in exhausted CD8+ T cells.

Area of Science:

• Immunology
• Molecular Biology
• Virology

Background:

• Sustained CD8+ T cell responses in chronic viral infections depend on stem-like precursor-exhausted T cells (TPEX).
• TPEX possess self-renewal capabilities and respond to PD-1 blockade, but methods to enhance them are limited.

Purpose of the Study:

• To investigate novel strategies for augmenting TPEX stemness and functionality to improve viral control.
• To elucidate the molecular mechanisms underlying TPEX stemness regulation.

Main Methods:

• Gene deficiency models (ZC3H12A, BCOR) to assess effects on TPEX.
• Analysis of TPEX proliferation, cell death, and stemness markers.
• Identification of key factors regulating the TPEX stemness program.

Main Results:

• ZC3H12A deficiency induced TPEX stemness but increased cell death; BCOR deficiency promoted TPEX proliferation.
• Combined BCOR and ZC3H12A targeting significantly enhanced TPEX stemness and functionality, improving viral control.
• Identified a core stemness program in TPEX, jointly suppressed by BCOR and ZC3H12A, involving novel factors like POU2F2.

Conclusions:

• BCOR and ZC3H12A collaboratively repress a core stemness program in TPEX.
• Targeting BCOR and ZC3H12A, or overexpressing POU2F2, represents a promising strategy to enhance antiviral immunity by boosting TPEX.
• This study reveals novel therapeutic targets for combating T cell exhaustion in chronic infections.