Activation-induced pyroptosis contributes to the loss of MAIT cells in chronic HIV-1 infected patients

Springer Science and Business Media LLC - Tập 9 - Trang 1-19 - 2022
Peng Xia1,2, Xu-Dong Xing3, Cui-Xian Yang4, Xue-Jiao Liao5, Fu-Hua Liu1,2, Hui-Huang Huang1, Chao Zhang1, Jin-Wen Song1, Yan-Mei Jiao1, Ming Shi1, Tian-Jun Jiang1, Chun-Bao Zhou1, Xi-Cheng Wang4, Qing He5, Qing-Lei Zeng2, Fu-Sheng Wang1, Ji-Yuan Zhang1
1Senior Department of Infectious Diseases, the Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China
2Department of Infectious Diseases and Hepatology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
3Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Peking University, Beijing, China
4Yunnan Infectious Disease Hospital, Kunming, China
5the Third People’s Hospital of Shenzhen, School of Medicine, Southern University of Science and Technology, Shenzhen, China

Tóm tắt

Mucosal-associated invariant T (MAIT) cells are systemically depleted in human immunodeficiency virus type 1 (HIV-1) infected patients and are not replenished even after successful combined antiretroviral therapy (cART). This study aimed to identify the mechanism underlying MAIT cell depletion. In the present study, we applied flow cytometry, single-cell RNA sequencing and immunohistochemical staining to evaluate the characteristics of pyroptotic MAIT cells in a total of 127 HIV-1 infected individuals, including 69 treatment-naive patients, 28 complete responders, 15 immunological non-responders, and 15 elite controllers, at the Fifth Medical Center of Chinese PLA General Hospital, Beijing, China. Single-cell transcriptomic profiles revealed that circulating MAIT cells from HIV-1 infected subjects were highly activated, with upregulation of pyroptosis-related genes. Further analysis revealed that increased frequencies of pyroptotic MAIT cells correlated with markers of systemic T-cell activation, microbial translocation, and intestinal damage in cART-naive patients and poor CD4+ T-cell recovery in long-term cART patients. Immunohistochemical staining revealed that MAIT cells in the gut mucosa of HIV-1 infected patients exhibited a strong active gasdermin-D (GSDMD, marker of pyroptosis) signal near the cavity side, suggesting that these MAIT cells underwent active pyroptosis in the colorectal mucosa. Increased levels of the proinflammatory cytokines interleukin-12 (IL-12) and IL-18 were observed in HIV-1 infected patients. In addition, activated MAIT cells exhibited an increased pyroptotic phenotype after being triggered by HIV-1 virions, T-cell receptor signals, IL-12 plus IL-18, and combinations of these factors, in vitro. Activation-induced MAIT cell pyroptosis contributes to the loss of MAIT cells in HIV-1 infected patients, which could potentiate disease progression and poor immune reconstitution.

Tài liệu tham khảo

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