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.
Metrics
-
- 4,897
- views
-
- 441
- downloads
-
- 18
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
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
-
- Immunology and Inflammation
Chronic antigenic stimulation can trigger the formation of interleukin 10 (IL-10)-producing T-regulatory type 1 (TR1) cells in vivo. We have recently shown that murine T-follicular helper (TFH) cells are precursors of TR1 cells and that the TFH-to-TR1 cell transdifferentiation process is characterized by the progressive loss and acquisition of opposing transcription factor gene expression programs that evolve through at least one transitional cell stage. Here, we use a broad range of bulk and single-cell transcriptional and epigenetic tools to investigate the epigenetic underpinnings of this process. At the single-cell level, the TFH-to-TR1 cell transition is accompanied by both, downregulation of TFH cell-specific gene expression due to loss of chromatin accessibility, and upregulation of TR1 cell-specific genes linked to chromatin regions that remain accessible throughout the transdifferentiation process, with minimal generation of new open chromatin regions. By interrogating the epigenetic status of accessible TR1 genes on purified TFH and conventional T-cells, we find that most of these genes, including Il10, are already poised for expression at the TFH cell stage. Whereas these genes are closed and hypermethylated in Tconv cells, they are accessible, hypomethylated, and enriched for H3K27ac-marked and hypomethylated active enhancers in TFH cells. These enhancers are enriched for binding sites for the TFH and TR1-associated transcription factors TOX-2, IRF4, and c-MAF. Together, these data suggest that the TR1 gene expression program is genetically imprinted at the TFH cell stage.
-
- Genetics and Genomics
- Immunology and Inflammation
Systemic lupus erythematosus (SLE) is an autoimmune disease, the pathophysiology and genetic basis of which are incompletely understood. Using a forward genetic screen in multiplex families with SLE, we identified an association between SLE and compound heterozygous deleterious variants in the non-receptor tyrosine kinases (NRTKs) ACK1 and BRK. Experimental blockade of ACK1 or BRK increased circulating autoantibodies in vivo in mice and exacerbated glomerular IgG deposits in an SLE mouse model. Mechanistically, NRTKs regulate activation, migration, and proliferation of immune cells. We found that the patients’ ACK1 and BRK variants impair efferocytosis, the MERTK-mediated anti-inflammatory response to apoptotic cells, in human induced pluripotent stem cell (hiPSC)-derived macrophages, which may contribute to SLE pathogenesis. Overall, our data suggest that ACK1 and BRK deficiencies are associated with human SLE and impair efferocytosis in macrophages.
