Effector CD8 T cell differentiation in primary and breakthrough SARS-CoV-2 infection in mice.

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.