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Long COVID manifests with T cell dysregulation, inflammation and an uncoordinated adaptive immune response to SARS-CoV-2
  Jan 11 2024 Download the PDF here
In summary, using multiple 'omics' analytical approaches, we found that LC individuals exhibited phenotypic perturbations in both total and SARS-CoV-2-specific CD4+ and CD8+ T cells and changes in gene expression among CD4+ T cells, CD8+ T cells, monocytes and B cells. We found higher proportions of CD4+ TCM cells, TFH cells and Treg cells in LC compared to R individuals. SARS-CoV-2-specific CD8+ T cells, but not total CD8+ T cells, more frequently expressed the exhaustion markers PD1 and CTLA4, consistent with ongoing stimulation by viral antigens. Further supporting a potential persistent reservoir was our observation of higher SARS-CoV-2 antibody levels in LC individuals, consistent with reports of higher spike-specific IgG in LC compared to R individuals9. CyTOF, flow cytometry and scRNA-seq indicated that CD4+ T cells from LC individuals preferentially expressed CXCR4, CXCR5 and CCR6. CXCR4 expression is elevated on bystander CD4+ and CD8+ T cells in fatal COVID-19 (ref. 4) and on pulmonary CD4+ T cells, B cells, macrophages and granulocytes in the context of LC following SARS-CoV-2 infection of mice10. Although fully recovered individuals exhibited coordinated humoral and cellular immune responses to SARS-CoV-2, this coordination was lost in LC individuals, consistent with observations that about half of individuals with LC with no detectable SARS-CoV-2 antibodies have detectable SARS-CoV-2-specific T cell responses11. How the humoral response becomes divorced from the cellular response is unclear, but could involve a misalignment between IL-4 and IL-5 production by TH2 cells, as indicated by our Olink analysis.
Long COVID (LC) occurs after at least 10% of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, yet its etiology remains poorly understood. We used 'omic" assays and serology to deeply characterize the global and SARS-CoV-2-specific immunity in the blood of individuals with clear LC and non-LC clinical trajectories, 8 months postinfection. We found that LC individuals exhibited systemic inflammation and immune dysregulation. This was evidenced by global differences in T cell subset distribution implying ongoing immune responses, as well as by sex-specific perturbations in cytolytic subsets. LC individuals displayed increased frequencies of CD4+ T cells poised to migrate to inflamed tissues and exhausted SARS-CoV-2-specific CD8+ T cells, higher levels of SARS-CoV-2 antibodies and a mis-coordination between their SARS-CoV-2-specific T and B cell responses. Our analysis suggested an improper crosstalk between the cellular and humoral adaptive immunity in LC, which can lead to immune dysregulation, inflammation and clinical symptoms associated with this debilitating condition.

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