In a recent study in the Proceedings of the National Academy of Sciences (PNAS), researchers look at T-cell reactivity after recovery from coronavirus disease 2019 (COVID-19).
Study: Transient and long-lasting T-cell reactivity after COVID-19. Image credit: UGREEN 3S / Shutterstock.com
background
Naive cluster of differentiating T 4-positive (CD4+) lymphocytes differentiate into antigen-specific effector cells and memory T helper (TH) cells after antigen encounter. TH 1-polarized cells produce interferon γ (IFN-γ) and interleukin 2 (IL-2), subsequently leading to cell-mediated clearance of viruses and other intracellular pathogens.
Instead, TH 2 cells produce IL-4 and IL-13, thus facilitating B-cell activity and promoting post-infection tissue repair. Similarly, naïve CD8+ T lymphocytes differentiate into effector memory, central memory, and effector cells that exhibit cytotoxicity against virus-infected cells.
About the study
The present study determined severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T-cell reactivity. Whole blood samples were collected from healthy subjects recovered from COVID-19 between one and 21 months after recovery.
Antigen-specific TH cell cytokines were analyzed in samples after ex vivo stimulation with peptides spanning the N-terminus of SARS-CoV-2 spike protein 1 (S1) or the complete nucleocapsid.
Results of the study
The samples were found to generate TH 2-type cytokines IL-4 and IL-13 in response to nucleocapsid peptides up to 70 days after recovery from COVID-19. These responses were not detected in unstimulated blood samples or in peptide-stimulated uninfected control samples. This initial TH 2 response was concurrent with a TH 17-type response.
In particular, levels of TH 2 and TH 17 cytokines induced by nucleocapsid were highly correlated. Results were similar when S1 peptides stimulated whole blood samples.
Furthermore, the induction of IL-12 by S1 peptides and nucleocapsid was contemporaneous with the levels of IL-4, IL-13, and IL-17 in the first months after infection. The striking correlation between the levels of these cytokines in the early phase of infection suggests that they were produced by the same T cells.
Follicular helper T cells (TFH), which transcribe numerous cytokine genes, were also analyzed to explore a unified T cell phenotype that was responsible for producing these cytokines. However, the induction of IL-21, which is the signature cytokine of TFH cells, after stimulation by either group of peptides was weak. This finding implies that IL-21+ TFH cells might not have been the source of the multipolar cytokine response.
S1- and nucleocapsid-induced IFN-γ and IL-2 were induced in the first months after infection and showed poor or no correlation with the levels of IL-4, IL-12, IL13, and IL- 17. However, these cytokines persisted without decreasing over time and correlated well. Thus, SARS-CoV-2-specific T-cell responses during the early and late convalescent phases are derived from distinct/separate T-cell clones.
Conclusions
The durability of IFN-γ and IL-2 responses reported in the current study indicates a sustained memory T-cell response after SARS-CoV-2 infection. This was congruent with recent reports that revealed the memory response of CD4+ and CD8+ reactive T cells to SARS-CoV-2 after infection.
These studies estimated that the half-life of the memory T-cell response is three to five months after recovery from COVID-19. Comparatively, the results of the current study suggest that SARS-CoV-2-reactive IL-2- or IFN-γ-producing T cells could prevail much longer than previously reported.
A subset of specialized T cells (Th1 cells) that promote the destruction of virus-infected cells was observed to be active for at least 20 months after natural COVID-19. The infected patients also had several other types of T cells that reacted with SARS-CoV-2. These latter T cells disappeared from the blood approximately two months after recovery from infection.
Anna Martner, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg. Photo: Elin Lindström
“While certain T cell subsets disappear soon after infection, highly specialized T cells (helper T cells 1) remain stably present in the blood to suggest that a vital aspect of protective immunity is functional years after COVID-19,” says Anna Martner, Associate Professor of Immunology at the Sahlgrenska Academy. “These results may explain why re-infection with SARS-CoV-2 rarely results in severe COVID-19.”
Some limitations of the study include its small sample size and short post-COVID-19 follow-up period. Furthermore, the investigators did not explicitly identify the cytokine-producing T cell phenotypes.
Journal reference:
- Martner, A., Wiktorin HG, Törnell, A., et al. (2022). Transient and long-lasting T-cell reactivity after COVID-19. Proceedings of the National Academy of Sciences 119(30). doi:10.1073/pnas.2203659119