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

While cGAS is known as a cytosolic DNA sensor in innate immunity, its function in T cells and adaptive immunity remains uncharacterized. This study investigates the role of cGAS in regulatory T (T reg ) cells. At steady state, cGAS is located in the nucleus of T reg cells, while stimulation of naive CD4 + T cell induces its transcription and translocation into the nucleus. Using T cell and T reg cell-specific cGAS knockout mice, we demonstrate that nuclear cGAS promotes T reg cell development and function independently of its downstream adaptor STING. cGAS primes thymocytes for T reg cell differentiation during positive selection and stabilizes FOXP3. Mechanistically, nuclear cGAS recruits chromatin organizer CTCF to Tnfrsf9 (4-1BB) and Tnfrsf4 (OX40) loci via chromatin interaction to sustain their expression and TCR signaling. T reg cell-specific cGAS deletion impairs tumor growth in mice. This work reveals a STING-independent role for nuclear cGAS in adaptive immunity, establishing a cGAS-CTCF axis controlling T reg cell-mediated immune tolerance.