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Yichuan Xiao's and Mingyue Zheng’s group reveals a new DNA-sensing pathway in CD4+ T cells and its regulatory mechanism in mediating aging-related autoimmune disease

 

On March 4, 2021, the international academic journal Immunity published online the collaborative research paper "Cytoplasmic DNA sensing by KU complex in aged CD4+ T cells potentiates T cell activation and aging-related autoimmune inflammation" by Yichuan Xiao's group at the Shanghai Institute of Nutrition and Health and Mingyue Zheng's researcher at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences. This study reveals that the KU complex mediated-DNA sensing in CD4+ T cells potentiates aging-related autoimmune diseases.

The aging of the population is a major social issue in China and worldwide, and with aging, the normal organism will exhibit an aging state, and the aging of the immune system is one of the prominent and important issues, which is also an important cause of chronic inflammation and autoimmune diseases in the elderly individuals. Although thymus atrophy causes a decrease in naive T cell output, the number of peripheral T cells does not decrease in older individuals because of its homeostatic proliferation and activation in the aging state, however, the specific regulatory mechanism by which aging promotes homeostatic proliferation of T cells and thus promotes the development of autoimmune inflammation is unknown.

In this study, the researchers found that there is a huge accumulation of DNA in the cytoplasm of CD4+ T cells of aged mice and humans, and that this accumulated DNA promotes the proliferation and activation of TCR-induced CD4+ T cells, suggesting that T cells DNA sensing promote their functional activation. Then, the proteins that bind to in T cell cytoplasmic DNA were screened by mass spectrometry combined with immunoblotting and found that DNA in T cells does not bind to cGAS, but to KU complex (KU70/KU80). If the binding of the KU complex to DNA was blocked using the small molecule inhibitor STL127705, the proliferation and activation of DNA-induced CD4+ T cells were significantly inhibited, which in turn alleviated the development of autoimmune inflammation in aged mice, indicating that DNA-induced functional activation of T cells is indeed mediated by DNA sensing through the KU complex. Typically, the KU complex, together with the catalytic subunits of DNA-dependent protein kinases (DNA-PKcs), functions in the nucleus to mediate DNA damage repair. Further studies revealed that the KU complex was abundantly expressed in the cytoplasm of T cells, and its recognition of DNA in CD4+ T cells promoted the activation of DNA-PKcs phosphorylation, which in turn mediated the phosphorylation of ZAK at T169, and the phosphorylated ZAK then activated the downstream AKT/mTOR pathway, thus enhancing the proliferation and activation of CD4+ T cells. Thus, activation of the KU complex-mediated DNA-sensing pathway in CD4+ T cells is a key mechanism leading to the development of autoimmune inflammation in aged mice.

To explore therapeutic strategies to interfere with this newly identified DNA-sensing pathway and thereby suppress aging-associated autoimmune inflammation, researchers treated aged mice with Caloric Restriction (CR) or Fast-Mimicking Diet (FMD) and found that both modes of dieting significantly reduced DNA damage and cytoplasmic DNA accumulation in aged mouse CD4+ T cells, thereby inhibiting ZAK-T169 phosphorylation and activation of downstream AKT/mTOR signaling, which ultimately suppressed CD4+ T cell activation and aging-associated autoimmune disease. Furthermore, based on the identified key protein kinase ZAK in the DNA sensing pathway, the researchers applied deep learning combined with molecular simulation to screen a library of approximately 130,000 compounds and obtained iZAK2, a small molecule compound that specifically inhibits ZAK kinase activity. iZAK2 was found to effectively inhibit DNA-induced CD4+ T cell proliferation and activation, thereby alleviating the pathological symptoms of autoimmune disease in aged mice.


Schematic representation of the cartoon and mechanism of DNA sensing in aged CD4+ T cells promoting its activation and autoimmune inflammation

Taken together, this study reveals a novel DNA-sensing pathway in aged CD4+ T cells that is independent on cGAS/STING, which promotes T cell activation and proliferation and leads to the development of aging-associated autoimmune diseases. Further investigation and development of inhibitors that block DNA-sensing signaling in T cells may be beneficial for clinical treatment of aging-related autoimmune diseases. Following the publication of the paper, the Immunity journal in the same issue also commented the findings as a Preview, highlighting the discovery of a novel KU receptor that senses cytoplasmic DNA in T cells.

Yan Wang, a PhD student at the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, is the first author of the paper, and Yichuan Xiao and Mingyue Zheng are co-corresponding authors of this study. This work was supported and assisted by Prof. Hongbing Shu and Prof. Bo Zhong from Wuhan University, Prof. Tao Li from National Center of Biomedical Analysis (Beijing), Prof. Pinglong Xu from Zhejiang University, Prof. Hui Xiao from Shanghai Pasteur Institute of Chinese Academy of Sciences, Prof. Baoxue Ge from Tongji University and Prof. Xing Chang from West Lake University. The research was also supported by projects from the Ministry of Science and Technology, the National Natural Science Foundation of China and the Chinese Academy of Sciences, as well as by the public technology platform and animal facility of the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences.

Links: https://www.cell.com/immunity/fulltext/S1074-7613(21)00069-8