Editors' ChoiceImmunology

Aging and autoimmunity

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Science Signaling  20 Apr 2021:
Vol. 14, Issue 679, eabj0430
DOI: 10.1126/scisignal.abj0430

Cytoplasmic DNA sensing by the KU complex enhances CD4+ T cell activation and contributes to aging-induced autoimmunity.

Aging is associated with an increased risk of developing autoimmune disease. Compared to younger individuals, the elderly exhibit increased proliferation of naïve T cells in the periphery. In addition, aging correlates with increased amounts of DNA in the circulation, which is also associated with autoimmunity. Wang et al. showed in aged human and mouse CD4+ T cells that DNA accumulated in the cytoplasm, which led to enhanced cellular activation and proliferation. In mice with experimental autoimmune encephalitis (EAE), a model of multiple sclerosis, disease symptoms were more severe in mice that received aged CD4+ T cells compared to those that received young cells. Cytoplasmic DNA in CD4+ T cells was sensed by the KU complex, which, together with the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), repairs breaks in nuclear DNA. Loss of components of the cGAS-STING pathway, which detects cytosolic DNA in other contexts, did not affect the DNA-induced activation or proliferation of CD4+ T cells. DNA-induced activation of DNA-PKcs led to the recruitment and activation of the kinase ZAK, which in turn activated the kinase Akt, leading to cellular proliferation. Targeting ZAK activation specifically inhibited the DNA-dependent activation of CD4+ T cells in vitro. The authors developed a specific ZAK inhibitor, which blocked DNA-induced CD4+ T cell proliferation in vitro and ameliorated the symptoms of EAE in aged mice. Together, these data suggest that the KU complex senses accumulated DNA in aged CD4+ T cells and that targeting the kinase ZAK may be a therapy to treat age-related autoimmunity.

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