Long COVID manifests with T cell dysregulation, inflammation, and an uncoordinated adaptive immune response to SARS-CoV-2

Long COVID, a type of post-acute sequelae of SARS-CoV-2 infection (LC), occurs after at least 10% of SARS-CoV-2 infections, yet its etiology remains poorly understood. Here, we used multiple “omics” assays (CyTOF, RNAseq, Olink) and serology to deeply characterize both global and SARS-CoV-2-specific immunity from blood of unvaccinated individuals with clear LC and non-LC clinical trajectories, 8 months following infection. Our analysis focused on deep phenotyping of T cells, which play important roles in immunity against SARS-CoV-2 yet may also contribute to COVID-19 pathogenesis. Our findings demonstrate that LC individuals exhibit systemic inflammation and immune dysregulation. This is evidenced by global differences in T cell subset distribution in ways that imply ongoing immune responses, as well as by sex-specific perturbations in cytolytic subsets. LC individuals harbored increased frequencies of CD4+ T cells poised to home to inflamed tissues, and of exhausted SARS-CoV-2-specific CD8+ T cells. They also harbored significantly higher levels of SARS-CoV-2 antibodies, and they, but not non-LC individuals, exhibited a mis-coordination between their SARS-CoV-2-specific T and B cell responses. Collectively, our data suggest that proper crosstalk between the humoral and cellular arms of adaptive immunity has broken down in LC, and that this, perhaps in the context of a persistent reservoir of SARS-CoV-2, leads to the immune dysregulation, inflammation, and clinical symptoms associated with this debilitating disease. To study the phenotypes and effector functions of immune cells from individuals experiencing Long COVID-19 symptoms, we analyzed blood samples from 27 LC and 16 non-LC participants from the San Francisco-based Long-term Impact of Infection with Novel Coronavirus (LIINC) cohort. RNA-seq experiments were perfomed on the blood specimens fromour cohort of LC and non-LC participants.