tetano
Editor, Senior Moderator
Commun Biol
. 2025 Mar 8;8(1):392.
doi: 10.1038/s42003-025-07820-7. Effector CD8 T cell differentiation in primary and breakthrough SARS-CoV-2 infection in mice
Brock Kingstad-Bakke[SUP] 1 [/SUP], Woojong Lee[SUP] 1 [/SUP], Boyd L Yount Jr[SUP] 2 [/SUP], Thomas Cleven[SUP] 1 [/SUP], Hongtae Park[SUP] 1 [/SUP], Jeremy A Sullivan[SUP] 1 [/SUP], Ralph C Baric[SUP] 2 [/SUP], M Suresh[SUP] 3 [/SUP]
Affiliations
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 CD45RO[SUP]+[/SUP]HLA-DR[SUP]+[/SUP] 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.
. 2025 Mar 8;8(1):392.
doi: 10.1038/s42003-025-07820-7. Effector CD8 T cell differentiation in primary and breakthrough SARS-CoV-2 infection in mice
Brock Kingstad-Bakke[SUP] 1 [/SUP], Woojong Lee[SUP] 1 [/SUP], Boyd L Yount Jr[SUP] 2 [/SUP], Thomas Cleven[SUP] 1 [/SUP], Hongtae Park[SUP] 1 [/SUP], Jeremy A Sullivan[SUP] 1 [/SUP], Ralph C Baric[SUP] 2 [/SUP], M Suresh[SUP] 3 [/SUP]
Affiliations
- PMID: 40057586
- PMCID: PMC11890755
- 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 CD45RO[SUP]+[/SUP]HLA-DR[SUP]+[/SUP] 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.