Prolonged T-cell activation and long COVID symptoms independently associate with severe COVID-19 at 3 months
- University of Bristol, United Kingdom
- North Bristol NHS Trust, United Kingdom
- University Hospitals Bristol and Weston NHS Foundation Trust, United Kingdom
Abstract
COVID-19 causes immune perturbations which may persist long-term, and patients frequently report ongoing symptoms for months after recovery. We assessed immune activation at 3-12 months post hospital admission in 187 samples from 63 patients with mild, moderate or severe disease and investigated whether it associates with long COVID. At 3 months, patients with severe disease displayed persistent activation of CD4+ and CD8+ T-cells, based on expression of HLA-DR, CD38, Ki67 and granzyme B, and elevated plasma levels of IL-4, IL-7, IL-17 and TNF-α compared to mild and/or moderate patients. Plasma from severe patients at 3 months caused T-cells from healthy donors to upregulate IL-15Rα, suggesting that plasma factors in severe patients may increase T-cell responsiveness to IL-15-driven bystander activation. Patients with severe disease reported a higher number of long COVID symptoms which did not however, correlate with cellular immune activation/pro-inflammatory cytokines after adjusting for age, sex and disease severity. Our data suggests that long COVID and persistent immune activation may correlate independently with severe disease.
Data availability
All data generated or analysed during this study are included in the manuscript files or supplementary files. Raw file (FCS files) for all flow cytometry data have been deposited in the FlowRepository, the link for access to the data is provided in the Material and Methods, Flow cytometry data analysis section.The code script and data for the analysis in Figure 6 are publicly available here: https://github.com/gushamilton/discover_long_covid. The link is provided in the Material and Methods, statistical analysis section.
Article and author information
Author details
Michaela Gregorova
Funding
Wellcome Trust (Elizabeth Blackwell Institute (EBI) with funding from the University's alumni and friends)
- Anu Goenka
- Linda Wooldridge
- Laura Rivino
Southmead Hospital Charity (DISCOVER)
- Fergus Hamilton
- David Arnold
- Laura Rivino
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: Information regarding our ethics approval and consent process is provided in the Materials and Methods section and copied below.Patients hospitalized with COVID-19 ({greater than or equal to}18 years of age) were recruited between 30th March and 3rd June 2020 into the observational study DIagnostic and Severity markers of COVID-19 to Enable Rapid triage (DISCOVER), a single-centre prospective study based in Bristol (UK). Research Ethics Committee (REC) approval: REC:20/YH/1021. Survivors were invited at 3, 8 and 12 months post admission to attend outpatient follow up clinics for a systematic clinical assessment (Arnold et al 2020). For those patients attending a face-to-face follow-up, consent was taken to collect samples for research purposes (blood for PBMC isolation, plasma and serum). When available serum collected from patients at admission was made available to the research team.
Copyright
© 2023, Santopaolo et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Prolonged T-cell activation and long COVID symptoms independently associate with severe COVID-19 at 3 months
eLife 12:e85009.
https://doi.org/10.7554/eLife.85009
Further reading
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During thymic development, most γδ T cells acquire innate-like characteristics that are critical for their function in tumor surveillance, infectious disease, and tissue repair. The mechanisms, however, that regulate γδ T cell developmental programming remain unclear. Recently, we demonstrated that the SLAM/SAP signaling pathway regulates the development and function of multiple innate-like γδ T cell subsets. Here, we used a single-cell proteogenomics approach to identify SAP-dependent developmental checkpoints and to define the SAP-dependent γδ TCR repertoire in mice. SAP deficiency resulted in both a significant loss of an immature Gzma+Blk+Etv5+Tox2+ γδT17 precursor population and a significant increase in Cd4+Cd8+Rorc+Ptcra+Rag1+ thymic γδ T cells. SAP-dependent diversion of embryonic day 17 thymic γδ T cell clonotypes into the αβ T cell developmental pathway was associated with a decreased frequency of mature clonotypes in neonatal thymus, and an altered γδ TCR repertoire in the periphery. Finally, we identify TRGV4/TRAV13-4(DV7)-expressing T cells as a novel, SAP-dependent Vγ4 γδT1 subset. Together, the data support a model in which SAP-dependent γδ/αβ T cell lineage commitment regulates γδ T cell developmental programming and shapes the γδ TCR repertoire.
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Here, we sequenced rearranged TCRβ and TCRα chain sequences in CD4+CD8+ double positive (DP), CD4+CD8- single positive (SP4) and CD4-CD8+ (SP8) thymocyte populations from the foetus and young adult mouse. We found that life-stage had a greater impact on TCRβ and TCRα gene segment usage than cell-type. Foetal repertoires showed bias towards 3’TRAV and 5’TRAJ rearrangements in all populations, whereas adult repertoires used more 5’TRAV gene segments, suggesting that progressive TCRα rearrangements occur less frequently in foetal DP cells. When we synchronised young adult DP thymocyte differentiation by hydrocortisone treatment the new recovering DP thymocyte population showed more foetal-like 3’TRAV and 5’TRAJ gene segment usage. In foetus we identified less influence of MHC-restriction on α-chain and β-chain combinatorial VxJ usage and CDR1xCDR2 (V region) usage in SP compared to adult, indicating weaker impact of MHC-restriction on the foetal TCR repertoire. The foetal TCRβ repertoire was less diverse, less evenly distributed, with fewer non-template insertions, and all foetal populations contained more clonotypic expansions than adult. The differences between the foetal and adult thymus TCR repertoires are consistent with the foetal thymus producing αβT-cells with properties and functions that are distinct from adult T-cells: their repertoire is less governed by MHC-restriction, with preference for particular gene segment usage, less diverse with more clonotypic expansions, and more closely encoded by genomic sequence.
