期刊
IMMUNITY
卷 54, 期 4, 页码 632-+出版社
CELL PRESS
DOI: 10.1016/j.immuni.2021.02.003
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类别
资金
- Strategic Priority Research Program of the Chinese Academy of Sciences [XDB39030300]
- National Key R&D Program of China [2018YFA0107201, 2018YFA0902703]
- National Natural Science Foundation of China [82030041, 81770567]
- Program of Shanghai Academic/Technology Research Leader [20XD1424600]
- 111 program [D20036]
- CAS Key Laboratory of Tissue Microenvironment and Tumor
The study reveals that the KU complex is abundantly expressed in CD4(+) T cells and enhances cell activation and proliferation in aged mice with EAE pathology by facilitating DNA-PKcs recruitment and phosphorylation of the kinase ZAK. A specific ZAK inhibitor can alleviate EAE pathology in aged mice.
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.
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