T cell-intrinsic cGAS-CTCF regulation maintains regulatory T cell development and function

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• Cyclic GMP-AMP synthase (cGAS) is a known cytosolic DNA sensor in innate immunity.
• Its specific functions within T cells and adaptive immunity, particularly regulatory T (Treg) cells, are largely uncharacterized.

Purpose of the Study:

• To investigate the role of cGAS in the development and function of regulatory T (Treg) cells.
• To elucidate the mechanism by which cGAS influences Treg cell activity and adaptive immunity.

Main Methods:

• Utilized T cell and Treg cell-specific cGAS knockout mouse models.
• Analyzed cGAS localization and translocation upon stimulation in naive CD4+ T cells.
• Investigated the interaction of cGAS with chromatin modifiers like CTCF at specific gene loci (Tnfrsf9, Tnfrsf4).

Main Results:

• Nuclear cGAS promotes Treg cell development and function independently of STING.
• cGAS facilitates Treg cell differentiation during positive selection and stabilizes FOXP3 expression.
• cGAS recruits CTCF to the 4-1BB and OX40 loci, sustaining their expression and T cell receptor (TCR) signaling.
• Deletion of cGAS in Treg cells impaired tumor growth in mice.

Conclusions:

• Reveals a novel, STING-independent function of nuclear cGAS in adaptive immunity.
• Establishes a cGAS-CTCF axis that controls Treg cell-mediated immune tolerance.
• Highlights the potential of targeting the cGAS pathway in cancer immunotherapy.