Robust mucosal SARS-CoV-2-specific T cells effectively combat COVID-19 and establish polyfunctional resident memory in patient lungs
Airu Zhu, Chen Zhao, Qihong Yan, Mei Jiang, Xuesong Liu, Zhengtu Li, Na Li, Chunli Tang, Wenhua Jian, Jiangping He, Lan Chen, Jinling Cheng, Canjie Chen, Tian Tang, Zhiwei Xu, Qingtao Hu, Fang Li, Yanqun Wang, Jing Sun, Zhen Zhuang, Liyan Wen, Jianfen Zhuo, Donglan Liu, Yanjun Zhang, Xiaofang Huang, Suxiang Li, Qiuhui Zeng, Fangli Chen, Liang Zhou, Dongdong Liu, Changhao Zhong, Yu Chen, Shiyue Li, Kangli Liang, Na Zhong, Xinmei Zhang, Jiekai Chen, Jiekai Chen, Yonghao Xu, Nanshan Zhong, Jingxian Zhao, Jincun Zhao, Jingxian Zhao, Jincun Zhao
Abstract
Mucosal antigen-specific T cells are pivotal for pathogen clearance and immune modulation in respiratory infections. Dysregulated T cell responses exacerbate coronavirus disease 2019 severity, marked by cytokine storms and respiratory failure. Despite extensive description in peripheral blood, the characteristics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cells in the lungs remain elusive. Here we conducted integrated single-cell profiling of SARS-CoV-2-specific T cells in 122 bronchoalveolar lavage fluid (BALF) and 280 blood samples from 159 patients, including 27 paired BALF and blood samples from 24 patients. SARS-CoV-2-specific T cells were robustly elicited in BALF irrespective of prior vaccination, correlating with diminished viral loads, lessened systemic inflammation and improved respiratory function. SARS-CoV-2-specific T cells in BALF exhibited profound activation, along with proliferative and multi-cytokine-producing capabilities and a glycolysis-driven metabolic signature, which were distinct from those observed in peripheral blood mononuclear cells. After viral clearance, these specific T cells maintained a polyfunctional tissue-resident memory phenotype, highlighting their critical roles in infection control and long-term protection.