Kingstad-Bakke Brock, Lee Woojong, Yount Boyd L, Cleven Thomas, Park Hongtae, Sullivan Jeremy A, Baric Ralph C, Suresh M
Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, WI, USA.
Department of Microbiology and Immunology, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA.
Commun Biol. 2025 Mar 8;8(1):392. doi: 10.1038/s42003-025-07820-7.
The nature of the effector and memory T cell response in the lungs following acute SARS-CoV-2 infections remains largely unknown. To define the pulmonary T-cell response to COVID-19, we compared effector and memory T-cell responses to SARS-CoV-2 and influenza A virus (IAV) in mice. Both viruses elicited potent effector T cell responses in lungs, but memory T cells showed exaggerated contraction in SARS-CoV-2-infected mice. Specifically, unlike the T-bet/EOMES-driven effector transcription program in IAV lungs, SARS-CoV-2-specific CD8 T cells embarked on a STAT-3-centric transcriptional program, a defining characteristic of a pro-fibro-inflammatory program: limited cytotoxicity, diminished expression of tissue-protective inhibitory receptors (PD-1, LAG-3, and TIGIT), and augmented mucosal imprinting (CD103). Circulating CD45ROHLA-DR CD8 T cells in hospitalized COVID-19 patients expressed elevated levels of STAT-3 and low levels of TIGIT. IL-6 blockade experiments implicated IL-6 in STAT-3 induction and downregulation of PD-1 expression on SARS-CoV-2-specific primary effector CD8 T cells. Memory CD8 T cells specific to a single epitope, induced by mucosal vaccination, differentiated into cytotoxic effectors and expressed high levels of CD103, effectively reducing viral burden in lungs following a breakthrough SARS-CoV-2 infection. Our findings have implications for developing targeted immunotherapies to mitigate immunopathology and promote protective T cell immunity to SARS-CoV-2.
急性SARS-CoV-2感染后肺部效应T细胞和记忆T细胞反应的本质在很大程度上仍不清楚。为了明确肺部对COVID-19的T细胞反应，我们比较了小鼠对SARS-CoV-2和甲型流感病毒（IAV）的效应T细胞和记忆T细胞反应。两种病毒均在肺部引发了强烈的效应T细胞反应，但记忆T细胞在感染SARS-CoV-2的小鼠中出现了过度收缩。具体而言，与IAV感染肺部中由T-bet/EOMES驱动的效应转录程序不同，SARS-CoV-2特异性CD8 T细胞启动了以STAT-3为中心的转录程序，这是促纤维化炎症程序的一个决定性特征：细胞毒性有限、组织保护性抑制性受体（PD-1、LAG-3和TIGIT）表达减少以及黏膜印记（CD103）增强。住院COVID-19患者循环中的CD45RO HLA-DR CD8 T细胞表达高水平的STAT-3和低水平的TIGIT。IL-6阻断实验表明IL-6参与STAT-3的诱导以及SARS-CoV-2特异性初级效应CD8 T细胞上PD-1表达的下调。由黏膜疫苗诱导的针对单个表位的记忆CD8 T细胞分化为细胞毒性效应细胞并表达高水平的CD103，在SARS-CoV-2突破性感染后有效降低了肺部的病毒载量。我们的研究结果对开发靶向免疫疗法以减轻免疫病理学并促进对SARS-CoV-2的保护性T细胞免疫具有启示意义。
