Cytoplasmic DNA sensing by KU complex in aged CD4+ T cell potentiates T cell activation and agingrelated autoimmune inflammation

Aging is associated with DNA accumulation and increased homeostatic proliferation of circulating T cells.
Although these attributes are associated with aging-related autoimmunity, their direct contributions remain
unclear. Conventionally, KU complex, the regulatory subunit of DNA-dependent protein kinase (DNA-PK),
together with the catalytic subunit of DNA-PK (DNA-PKcs), mediates DNA damage repair in the nucleus.
Here, we found KU complex abundantly expressed in the cytoplasm, where it recognized accumulated cytoplasmic
DNA in aged human and mouse CD4+ T cells. This process enhanced T cell activation and pathology
of experimental autoimmune encephalomyelitis (EAE) in aged mice. Mechanistically, KU-mediated DNA
sensing facilitated DNA-PKcs recruitment and phosphorylation of the kinase ZAK. This activated AKT and
mTOR pathways, promoting CD4+ T cell proliferation and activation. We developed a specific ZAK inhibitor,
which dampened EAE pathology in aged mice. Overall, these findings demonstrate a KU-mediated cytoplasmic
DNA-sensing pathway in CD4+ T cells that potentiates aging-related autoimmunity.